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Extending autologous transplantation as first line therapy in multiple myeloma patients with severe renal impairment: a retrospective study by the SFGM-TC

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https://doi.org/10.1038/s41409-018-0122-8

A R T I C L E

Extending autologous transplantation as

first line therapy in

multiple myeloma patients with severe renal impairment: a

retrospective study by the SFGM-TC

Karine Augeul-Meunier1●Marie-Lorraine Chretien2●Anne-Marie Stoppa3●Lionel Karlin4●Lofti Benboubker5●

Jose Miguel Torregrosa Diaz6●Mohamad Mohty7●Ibrahim Yakoub-Agha8●Jacques-Olivier Bay9●

Aurore Perrot 10●Claude-Eric Bulabois11●Anne Huynh12●Mélanie Mercier13●Laurent Frenzel14 ●

Hervé Avet-Loiseau12●Régis Peffault de Latour15●Jérôme Cornillon1

Received: 16 June 2017 / Revised: 22 January 2018 / Accepted: 22 January 2018 / Published online: 9 March 2018 © Macmillan Publishers Limited, part of Springer Nature 2018

Abstract

Renal impairment is a common complication of multiple myeloma (MM), accounting for 20–30% of MM patients at diagnosis and 40–50% of patients during the course of their disease. This feature is associated with poor prognosis and shorter survival as compared to patients with normal renal function (NRF). Therefore, therapeutic management is challenging as autologous stem cell transplantation (ASCT) is often not considered as a valuable strategy, mainly due to concerns of toxicity. In this retrospective and multicenter study, we included 55 MM patients with dialysis-dependent or independent renal failure who underwent high-dose melphalan-based ASCT in order to assess the efficacy outcomes and toxicities of this strategy. Response to ASCT was at least VGPR (very good PR) in 58% of patients and 96% of patients who also received bortezomib-based induction were at least in PR after ASCT. Median OS was 76 months and median PFS was 55 months, similarly to MM patients with NRF. In multivariate analysis, dose of melphalan (140 mg/m2) was correlated with better PFS (18 months, P= 0.005). Toxicities included febrile neutropenia (75%) and severe mucositis (34%). Overall, this work confirmed that ASCT conditioned by 140 mg/m2 melphalan is a beneficial procedure for MM patients with renal failure.

Introduction

Renal impairment (RI) occurs in 20–30% of newly diag-nosed multiple myeloma (NDMM) patients, requiring dia-lysis for up to 10% of patients [1]. Kidney involvement at diagnosis is a pejorative factor for survival, reflecting

advanced disease and high tumor burden. Nevertheless, prognosis has improved during the recent years, due to best supportive care and bortezomib-based therapy. Median survival of patients with severe renal impairment has increased from 19 months before 2000 to 32 months after 2005 [2]. Association with high cut-off (HCO) dialysis can

* Jérôme Cornillon jerome.cornillon@icloire.fr

1 Institut de Cancérologie Lucien Neuwirth,

Saint-Priest-en-Jarez, France

2 Centre Hospitalo-Universitaire Dijon, Dijon, France 3 Institut Paoli Calmette, Marseille, France

4 Centre Hospitalier Lyon Sud, Lyon, France

5 Centre Hospitalo-Universitaire Bretonneau, Tours, France 6 Centre Hospitalo-Universitaire La Miletrie, Poitiers, France 7 Hôpital Saint-Antoine, Paris, France

8 CHU de Lille, LIRIC INSERM U995, Université Lille 2,

Lille, France

9 Centre Hospitalo-Universitaire Estaing, Clermont-Ferrand, France 10 Centre Hospitalo-Universitaire Vandoeuvre-les-Nancy,

Nancy, France

11 Centre Hospitalo-Universitaire Grenoble, Grenoble, France 12 Institut Universitaire du Cancer, Toulouse, France 13 Centre Hospitalo-Universitaire Angers, Angers, France 14 Hôpital Necker, Paris, France

15 Hôpital Saint-Louis, Paris, France

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also be helpful for renal recovery [3]. Hematological response is obviously the most important criteria for sur-vival improvement. Therefore, front line therapy for NDMM patients has to be optimal.

Recent results from the IFM (Intergroupe Francophone du Myélome) study confirmed the effectiveness of high-dose melphalan followed by autologous hematopoietic stem cell transplantation (ASCT) as first line therapy, in asso-ciation with a triplet bortezomib-imid-dexamethasone combination at induction and consolidation stages [4].

Actually, for patients with RI, no consensus is deter-mined and ASCT practice is not homogenous in the dif-ferent centers, in particular due to concerns of toxicity. Interestingly, several studies reported that ASCT could be feasible and effective in patients with RI, including dialysis-dependent myeloma patients [5–17]. Those results are yet limited, considering small sample size of patients, the het-erogeneity of renal failure severity and the absence of bortezomib-based induction.

The current retrospective study aimed at analyzing toxicity and outcome in a large cohort of 55 multiple myeloma (MM) patients with severe RI at diagnosis, as defined by creatinine clearance inferior to 30 mL/min, undergoing high-dose melphalan and ASCT, in the age of bortezomib.

Patients and methods

This study was approved by the SFGM-TC scientific council and was conducted in agreement with the declara-tion of Helsinki.

Patients

Patients were identified using the French cohort of ProMISE Database. We retrospectively included 55 patients present-ing with advanced renal failure at time of ASCT, from January 2002 to November 2012. The definition of renal failure was defined by creatinine clearance <30 mL/min, using the Cockroft-Gault equation. Patients with severe RI at diagnosis, but with renal recovery (creatinine clearance >30 mL/min) at ASCT were excluded. Database was reviewed for patients and disease characteristics, number of CD34 cells, melphalan dose, neutrophils and platelets recovery, hematological and renal response, graft-related toxicity, disease progression, and outcome.

Stem cell mobilization

All patients received prior induction therapy, bortezomib-based or other, according to centers’ practice at the time of transplantation. PBSC were mobilized using G-CSF alone

(at the dose of 10 µg/kg/day) or following

cyclophosphamide chemotherapy. A count of CD34+ cells was performed usingflow cytometry.

Conditioning regimen

All patients received melphalan-conditioning regimen. Melphalan dose was variable among centers, according to physician choice. Supportive cares were performed depending to centers’ practice. Patients received single or tandem ASCT as afirst or second line therapy for myeloma.

Study endpoints

Time to neutrophil engraftment was defined as the first of two consecutive days on which neutrophils exceeded 0.5 × 109/L. Time to platelet engraftment was defined as the first of 2 days with 20 × 109/L platelets without platelet trans-fusion during a 5-day period.

Disease progression or relapse (if complete remission had been achieved before ASCT) was defined by reap-pearance of signs of the disease with cytology or histology confirmation. Hematological and renal responses were assessed at approximately 100 days after ASCT, and at the date of the last follow-up. We designated non-relapse mortality (NRM) as death related to reasons other than relapse or progression. Overall survival (OS) was calculated from the date of ASCT to either the date of death from any cause or the last follow-up. Progression-free survival (PFS) was calculated from the date of ASCT to the date of pro-gression or date of death.

Hematologic response and progression were defined according to International Myeloma Working Group uni-form response criteria [18]. Renal response was defined according to International Myeloma Working Group criteria [1].

Graft-related toxicities including mucositis, infection, cardiac, and neurologic complications were graded according to Commune Terminology Criteria for Adverse Events (CTCAE), version 4.0.

Statistical methods

Study population was described using frequencies with associated percentage for qualitative data, and using median and range for quantitative data. Survival analysis was per-formed in univariate analysis using Kaplan–Meier methods and Log-Rank test (for OS and PFS), and using cumulative incidence for NRM and relapse risk, with relapse as a competing risk for the former and death in remission for the latter. In multivariate analysis, we performed a Cox pro-portional hazards regression model (for OS and PFS). Covariates were selected when p < 0.15 in univariate ana-lysis, and according to their clinical relevance. Analyses

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were performed using the statistical software R (v3.4) (http://www.r-project.org/).

Results

Patient characteristics

Characteristics of the 55 included patients are summarized in Table1. Median age was 61 years (range: 40–75). Thirty-nine patients (71%) presented free-light chain M.M. Majority of patients were ISS 3 (International Staging System). Among the 27 patients with cytogenetic data, 6 patients (32%) presented unfavorable cytogenetic profile (1 del(17p), 2 hypodiploidy and 3 del(13)). Renal biopsy was performed for 16 patients, showing major cases of cast nephropathy and Light Chain Deposition Disease (LCDD). Two patients presented arterionephrosclerosis lesions. Hypertension and diabetes antecedents were documented for 45 patients, as these comorbidities are known to be risk factors for renal insufficiency. Half of the patients presented hypertension (Table1).

Thirty-one patients (56%) received bortezomib-based induction therapy. Fourteen patients were treated with double ASCT. Forty-nine patients received ASCT as front-line therapy; whereas, six received ASCT as second front-line. However, four of them were transplanted during first year after diagnosis. Median time from diagnosis to ASCT was 5.3 months (range: 2.3–71).

Data relative to renal features at different steps of the study (i.e., at diagnosis and at ASCT) are presented in Table 1. Twenty-six patients were dialysis-dependent at diagnosis, 13 had clearance <10 mL/min, 12 had clearance ranging from 10 to 15 mL/min, and only 4 had clearance superior to 15 mL/min (max: 23 mL/min). Median clearance was 6 mL/min at diagnosis and 10.2 mL/min at ASCT (range: 6.5–30). Twenty-three patients were still dialysis-dependent at ASCT. The 24-h proteinuria was also docu-mented before and after ASCT in Table2.

Table 1 Baseline characteristics of patients

Population characteristics N= 55 Median age, years (range) 61 (40–75) Gender, n (%) Female 26 (47) Male 29 (53) Hypertension, n (%) Yes 22 (40) No 23 (42) Unknown 10 (18) Diabetes, n (%) Yes 4 (7) No 41 (75) Unknown 10 (18) Renal biopsy, n= 16 Cast nephropathy 10 (63) LCDD 3 (19) Arterionephrosclerosis 2 (12) Non-significant 1 (6)

Median follow-up, months (range) 55 (4–150) Median time to transplant, months (range) 5.3 (2.3–71) Paraprotein isotype, n (%)

IgG 11 (20)

IgA 2 (4)

IgD 3 (5)

Light Chain lambda 18 (33)

Light Chain kappa 19 (34)

Light Chain kappa+ lambda 2 (4) FISH/Cytogenetics risk, n Unfavorable 6 del(17p) 1 hypodiploidy 2 del(13) 3 Standard 21 Unknown 28 Bortezomib-based induction, n (%) 31 (56) Double ASCT, n (%) 14 (25)

Median number of CD34, x106/kg (range) 4 (0.47–10.7) Dose of Melphalan (mg/m2), n= 53

<140 10 (19%)

140 30 (57%)

140–195 6 (11%)

200 7 (13%)

Median clearance of creatinine at diagnosis (mL/min)

6

<10 13 (24%)

10–15 12 (22%)

>15 4 (7%)

Patients on dialysis at diagnosis, n (%) 26 (47)

Table 1 (continued)

Population characteristics N= 55 Median clearance of creatinine at ASCT (mL/min) 10

<10 3 (5%)

10–15 8 (15%)

>15 20 (37%)

Unknown 1

Patients on dialysis at ASCT, n (%) 23 (42) ASCT autologous stem cell transplantation, Ig immunoglogulin, LCDD light chain deposition disease

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Stem cell mobilization and hematopoietic recovery

Median number of grafted CD34+ cells was 4 × 106/kg (range: 0.47 to 10.7 × 106/kg). All patients received high-dose melphalan, ranging from 75 to 200 mg/m2, according to physicians’ choice. Nine patients received a dose <140 mg/m2, 30 patients received melphalan at 140 mg/m2, six received a dose ranging from 160 to 190 mg/m2, and eight received melphalan at 200 mg/m2. This data were lacking for two patients.

Treatment-related toxicity

Toxicities were summarized in Table 3. During ASCT hospitalization, 41 patients (75%) experienced hyperther-mia, with documented infection for 20 of them. Half of sepsis was gram-positive cocci bacteria related and quarter of sepsis was gram-negative bacilli bacteria related. We identified one patient who presented with Aspergillus infection, one with gram-positive bacilli and one with Clostridium difficile infection.

Thirty-seven (67%) presented mucositis which was severe (grade 3–4) for half of them (19/37). Two patients experienced grade 1–2 cardiac complications. Five patients experienced neurologic complications (three confusing episodes grade 1–2, one convulsive crisis grade 3 and one undocumented).

Three patients died during 100first days after ASCT: one from Aspergillus sepsis, one from cerebral bleeding during second ASCT and the last one from severe degradation of general status. Those two last were dialysis dependent. At day 100, the cumulative incidence of TRM was 6%.

Hematological recovery, response, and survival

Median delay for neutrophil recovery was 12 days (range: 10–34) and 16 days for platelet recovery (range: 7–331). After a median follow-up of 55 months (range: 4–150), median progression-free survival (PFS) was 51 months (range: 38.3–63.7) and median overall survival (OS) was

76 months (range: 66.4–85.6), as shown in Figs.1and2. In multivariate analysis, only dose of melphalan at 140 mg/m2 was significantly correlated with a better PFS (p = 0.005), compared to 100 mg/m2 (or less) and to >140 mg/m2(200 Table 2 Evolution of 24-h proteinuria before and after ASCT

24 h proteinuria (g/24 h) Before ASCT (n= 37, range 0.2–10.4) After ASCT (n= 33, range 0.08–3.5) <0.2 (non-significant) 0 8 0.2–0.5 11 8 0.5–1.0 7 10 1.0–2.0 4 5 2.0–5.0 10 2 >5.0 5 0

ASCT autologous stem cell transplantation

Table 3 Main toxicities during ASCT

N= 55

Febrile neutropenia 41 (75%)

Documented infection during neutropenia 20 (39%) Staphylococcus (epidermidis / aureus) 7 (6/1)

Streptococcus oralis 2 Enterococcus faecalis 2 Proteus mirabilis 1 Escherichia coli 1 Acinetobacter 1 Corynebacterium 1

Neceria subflava 1

Stenotrophomonas maltophila 1

Pseudomonas aeruginosa 1

Aspergillus 1

Clostridium difficile 1

Mucositis 37 (67%)

Grade 1–2 18 (33%)

Grade 3–4 19 (34%)

Cardiac toxicity (grade 1–2) 2 (4%)

Neurologic toxicity 5 (9%) Confusing episode 3 Convulsive crisis 1 Non-documented 1 TRM 3 (6%) Aspergillus sepsis 1 Cerebral bleeding 1

Severe denutrition and general status alteration 1 TRM toxicity-related mortality 140 120 100 80 60 40 20 0 1.0 0.8 0.6 0.4 0.2 0.0 n=53 Median: 51 months Censored Survival function Months Cum surv iv al

Progression free survival

Fig. 1 Progression-free survival (PFS) after ASCT for patients with renal impairment. Median PFS is 51 months

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mg/m2) (18, 75, and 31 months, respectively). Among the 51 patients that were evaluated for response, 12 patients (24%) were at least in very good partial response (VGPR) before ASCT, including 5 in complete response (CR). All of them were treated with bortezomib as induction therapy. After ASCT, 30 patients (58.8%) reached at least VGPR (22 CR and 8 VGPR). Among the 30 patients in VGPR or more post-ASCT, 22 (73%) were treated with bortezomib before ASCT. Table4showed responses.

During follow-up, 29 patients (54%) relapsed and 25 died. Main causes of death were relapse and disease pro-gression (72%).

Among the 23 patients on dialysis at time of ASCT, 10 patients (43%) reached CR after ASCT. Three patients achieved VGPR and 7 stayed in Partial Response (PR). One remained in stable disease (SD) and there were 2 unknown data. Thirteen patients (57% of patients on dialysis) were still alive at last time of follow-up, including nine patients without relapse (39% of patients on dialysis) and four patients experimenting at least one relapse. Median PFS was 73 months. Beyond 10 patients on dialysis who died, half of them were still on response at death time. Causes of death were sepsis or other toxicities after new treatment of relapse.

Renal response

Renal response was evaluated at 3 months after ASCT and at the last follow-up checkpoint. At 3 months, all dialysis-dependent patients at ASCT were still on dialysis (Table1). Ten patients presented minor renal response and one a partial renal response. Three patients became dialysis-dependent at this time without evidence of myeloma disease progression, probably due to natural tubulopathy progres-sion. All of them were in PR after ASCT.

At last follow-up, 13 patients remained dialysis-dependent and four were not evaluable (two early death, and two lacking data). Importantly, six patients (26%) were able to discontinue dialysis, without relapse and supple-mentary treatment for four of them. Eight patients became dialysis-dependent, related to disease progression. Nine patients improved their renal function, with a minor renal response. Proteinuria decreased for the majority of patients (60%), when comparing this variable before and after ASCT. Nevertheless, no correlation with renal response was found. Data are presented in Tables2 and5.

Discussion

Front-line therapy for NDMM presenting severe renal fail-ure remains challenging for hematologists, considering emergency of treatment and toxicity-related risk. Despite HCO dialysis and bortezomib-based therapy, RI remains a pejorative prognostic factor [3]. The use of high-dose melphalan followed by ASCT is known to be the gold standard for eligible NDMM, yet less administered to RI patients due to concerns of toxicity [4].

150 120 90 60 30 0 1.0 0.8 0.6 0.4 0.2 0.0 n= 52 Median: 76 months Censored Survival function Overall survival Cum survival Months

Fig. 2 Overall survival (OS) after ASCT for patients with renal impairment. Median OS is 76 months

Table 4 Quality of responses before and after ASCT Before ASCT CR VGPR PR SD PD 5 7 33 5 1 CR 22 5 5 10 2 0 After VGPR 8 0 2 5 1 0 ASCT PR 19 0 0 18 1 0 SD 2 0 0 0 1 1 PD 0 0 0 0 0 0

ASCT autologous stem cell transplantation, CR complete response, VGPR very good partial response, PR partial response, SD stable disease, PD progressive disease

Table 5 Evolution of 24 h proteinuria before and after ASCT 24 h proteinuria

(g/24 h)

Before ASCT (n=37, range 0.2–10.4)

After ASCT (n=33, range 0.08–3.5) <0.2 (non-significant) 0 8 0.2–0.5 11 8 0.5–1.0 7 10 1.0–2.0 4 2 2.0–5.0 10 2 >5.0 5 0

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Several studies reported that ASCT is feasible and is a safety procedure for MM patients with renal failure, but majority of them was conducted before bortezomib area and/or with very small sample size of patients [5–17]. We currently present the largest recent cohort of patients, all harboring a severe renal failure, including 23 patients still on dialysis at ASCT time, and 56% treated with bortezomib induction. This represents a large number of patients ben-efiting from modern induction therapy, compared to other recent studies in which induction treatment is often lacking or with a few number of patients treated with bortezomib.

The most important result of our study is the improve-ment of CR and VGPR after ASCT, including in the cohort of patients undergoing dialysis. The improvement of response after ASCT is the most reason for which ASCT stays the gold standard for the first line, even in modern treatment area given that PFS is supposed to be directly correlated to response [19]. In our study, 58% of patients reached at least VGPR after ASCT (43% of CR, 15% of VGPR), compared to 24% before ASCT. Those results are comparable to those of IFM 2005-01 study for bortezomib arm plus ASCT in NRF patients [20]. Interestingly, inferior to similar results were published from recent but smaller studies [8,16,17]. Yet, our study seems to highlight better results, probably due to larger bortezomib use. Hence, other recent papers confirmed the positive impact of bortezomib induction before ASCT, in RI population [21, 22]. How-ever, autologous transplantation still probably remains necessary to upgrade results. Indeed, our study shows better response rates compared to novel agents use alone. In Dimopoulos et al. [23] data, 63–82% of RI patients pre-sented at least PR using thalidomide, bortezomib, or lena-lidomide alone, without ASCT [23]. Of importance, in our study, 96% of patients were at least in PR after ASCT.

Response could also be improved by using modern three-regimen treatment for induction and consolidation after ASCT, as shown by Zanetti et al. [3] (61% of at least VGPR before ASCT when using VTD induction).

The second important result is survival improvement. With a median OS of 76 months and a median PFS of 55 months, our results are very impressive, at least com-parable to those obtained in IFM 2005-01 study for NRF patients [20]. In two recent studies, Sweiss et al. [17] and St Bernard et al. [16] confirmed that treatment free survival (TFS) and OS are improved by ASCT procedure, similar and even superior to those obtained for NRF patients con-cerning TFS. Considering novel agents (imids and borte-zomib) alone for RI patients, OS seems to be lower, ranging from 32 to 63 months [2,23], thus reinforcing the fact that novel agents combined with ASCT is a beneficial option for RI patients.

Independently to response and survival improvement, toxicities remained acceptable. In our study, febrile

neutropenia occurred in 75% of patients and severe muco-sitis in 34%. These results are comparable to those pre-viously published [5, 10, 12, 13, 16]. Indeed, it is well known that ASCT procedure for patients with renal impairment remains more toxic than for NRF, mostly con-cerning mucositis and febrile neutropenia, but also about neurologic and cardiac complications. Sweiss et al. [17] compared two groups of patients, based on renal function (sup or inf to 60 mL/min) and showed more toxicities in RI group, with longer platelet and neutrophil engraftment, more documented infections, more grade 4 mucositis and more grade 2–4 diarrhea. St Bernard et al. [16] also described frequent cardiac and neurologic toxicities (for 25% and 30% of patients, respectively), not found in NRF patients. However, we did not observe the same profile in our study. IMW Group recommends dose-adjusted mel-phalan (100–140 mg/m2) in order to manage ASCT-related toxicities for RI patients. Indeed, little is known about melphalan pharmacokinetics profile and it is considered that RI patients appear to have similar pharmacokinetics profile to those with NRF [17]. Nevertheless, melphalan is most often used at 140 mg/m2 dose, on the basis of published results showing less toxicity and same efficacy [5,8,17]. In our study, we found a significant survival benefit when using 140 mg/m2 dose, thus suggesting that this dose is a good compromise between toxicity and efficacy.

From previous studies, TRM and its definition are quite variable, ranging from 0 to 15%. It is often correlated to disease response at ASCT time. Hence, patients reaching only stable disease presented higher TRM [16], until 15%. In our study, all toxicities were exhaustively collected. Only three patients (6%) died during 100first days after ASCT. All deaths were reported as related to the treatment toxicity (infectious disease or bleeding). Moreover, one of them occurred after the second transplantation. This TRM remains higher than those observed for NRF patients, usually around 1–2% (1,7% in IFM study [4]).

Recent recommendations of IMWG for management of myeloma-related RI include ASCT as a feasible procedure with dose-adjusted melphalan (100–140 mg/m2) and borte-zomib regimen [1]. This procedure is recommended to fit patients. In our cohort, details of performance status at diagnosis or before ASCT were not documented, thereby producing a potential bias towards the selection of fit patients.

Regarding renal response, we observed that it remained low. However, six patients (16%) came off dialysis, far from ASCT, and independently of new treatment for four of them, corresponding to true renal recovery. Renal response is usually described as independently of myeloma response [23]. Furthermore, it is known that ASCT effect can be prolonged after the procedure and late delayed recovery was hence observed in other published results [8,16].

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Overall, high-dose melphalan (140 mg/m2) followed by ASCT appears to be a real benefit for MM patients with severe renal failure, including patients on dialysis. Interest-ingly, response was dramatically improved by this proce-dure, with median PFS similar to that of patients with NRF. Further prospective study using three-regimen induction and consolidation, together with MRD evaluation and main-tenance therapy, could determine a new first line gold standard therapy for NDMM patients with severe RI.

Compliance with ethical standards

Conflict of interest The authors declare that they have no conflict of interest.

References

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2. Dimopoulos MA, Delimpasi S, Katodritou E, Vassou A, Kyrt-sonis MC, Repousis P, et al. Significant improvement in the survival of patients with multiple myeloma presenting with severe renal impairment after the introduction of novel agents. Ann Oncol. 2014;25:195–200.

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12. Lee CK, Zangari M, Barlogie B, Fassas A, van Rhee F, Thertulien R, et al. Dialysis-dependent renal failure in patients with myeloma can be reversed by high-dose myeloablative therapy and auto-transplant. Bone Marrow Transplant. 2004;33:823–8.

13. Parikh GC, Amjad AI, Saliba RM, Kazmi SMA, Khan ZU, Lahoti A, et al. Autologous hematopoietic stem cell transplantation may reverse renal failure in patients with multiple myeloma. Biol Blood Marrow Transplant. 2009;15:812–6.

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Martinez R, et al. Are myeloma patients with renal failure can-didates for autologous stem cell transplantation? Hematol J. 2000;1:28–36.

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17. Sweiss K, Patel S, Culos K, Oh A, Rondelli D, Patel P. Melphalan 200 Mg/m2in patients with renal impairment is associated with increased short-term toxicity but improved response and longer treatment-free survival. Bone Marrow Transplant. 2016;51:1337–41.

18. Durie BG, Harousseau JL, Miguel JS, Bladé J, Barlogie B, Anderson K, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20:1467–73.

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20. Harousseau JL, Attal M, Avet-Loiseau H, Marit G, Caillot D, Mohty M, et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol. 2010;28:4621–9.

21. Breitkreutz I, Heiss C, Perne A, Beimler J, Jäger D, Egerer G, et al. Bortezomib improves outcome after SCT in multiple mye-loma patients with end-stage renal failure. Bone Marrow Trans-plant. 2014;49:1371–5.

22. Scheid C, Sonneveld P, Schmidt-Wolf IGH, van der Holt B, el Jarari L, Bertsch U, et al. Bortezomib before and after autologous stem cell transplantation overcomes the negative prognostic impact of renal impairment in newly diagnosed multiple mye-loma: a subgroup analysis from the HOVON-65/GMMG-HD4 trial. Haematologica. 2014;99:148–54.

23. Dimopoulos MA, Roussou M, Gkotzamanidou M, Nikitas N, Psimenou E, Mparmparoussi D, et al. The role of novel agents on the reversibility of renal impairment in newly diagnosed symp-tomatic patients with multiple myeloma. Leukemia. 2013;27:423–9.

Figure

Fig. 1 Progression-free survival (PFS) after ASCT for patients with renal impairment. Median PFS is 51 months
Fig. 2 Overall survival (OS) after ASCT for patients with renal impairment. Median OS is 76 months

Références

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