ASBMT. Autologous Stem Cell Transplantation: An Effective Salvage Therapy in Multiple Myeloma

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1 Biol Blood Marrow Transplant 19 (2013) 445e449 Autologous Stem Cell Transplantation: An Effective Salvage Therapy in Multiple Myeloma Emilie Lemieux 1,y, Cyrille Hulin 2,y, Denis Caillot 3, Stéphanie Tardy 2, Véronique Dorvaux 4, Jessica Michel 2, Thomas Gastinne 5, Cédric Rossi 3, Caroline Legouge 3, Cyrille Touzeau 5, Lucie Planche 5, Marion Loirat 5, Ingrid Lafon 3, Philippe Moreau 5, * ASBMT American Society for Blood and Marrow Transplantation 1 Hematology Department, University Hospital, Montreal, Canada 2 Hematology Department, University Hospital, Nancy, France 3 Hematology Department, University Hospital, Dijon, France 4 Hematology Department, University Hospital, Metz, France 5 Hematology Department, University Hospital, Nantes, France Article history: Received 5 September 2012 Accepted 19 November 2012 Key Words: Multiple myeloma Salvage therapy Autologous stem cell transplantation abstract Eighty-one patients treated with high-dose therapy and autologous stem cell transplantation (ASCT) as part of salvage therapy after a frontline ASCT were included in a retrospective analysis. The median time between the first and the salvage ASCT was 47 months. After salvage ASCT, 75 patients (93%) achieved at least a partial response, including 67% very good partial responses, and no toxic death was reported. Sixteen patients (20%) underwent consolidation therapy, whereas 30 patients (37%) underwent some form of maintenance therapy after salvage ASCT. For all patients, the median overall survival (OS) was 10 years from diagnosis and 4 years from salvage ASCT. The median progression-free survival (PFS) from the date of the first ASCT to the date of the first relapse was 40 months, and the median PFS from the date of salvage ASCT to the date of subsequent progression was 18 months. In the multivariate analysis of prognostic factors, three independent factors unfavorably affected PFS: a short duration of response to the first ASCT (cut-off value of 24 months), a response less than a very good partial response after salvage therapy, and no maintenance treatment after salvage ASCT. Age over 60 years and a short duration of response after the first ASCT were the two factors adversely affecting OS from the time of diagnosis and OS from the time of salvage ASCT. Our data show that salvage ASCT is a feasible option that should be routinely considered at the time of relapse for patients with a response duration of more than 2 years to frontline high-dose therapy. Ó 2013 American Society for Blood and Marrow Transplantation. INTRODUCTION Autologous stem cell transplantation (ASCT) after highdose melphalan is the treatment of choice for patients with symptomatic multiple myeloma (MM) who are younger than 65 years of age [1,2]. The incorporation of novel agents into this strategy has markedly improved progression-free survival (PFS) and overall survival (OS) of this group of patients over the last decade [3]. Nevertheless, almost all patients ultimately relapse, and no plateau is observed in the survival curves. At the time of disease recurrence, no one standard salvage approach is available; instead, various therapeutic options are used, including novel agentebased therapy, administered for a fixed duration of time or until progression. In a pivotal trial for the approval of bortezomib as monotherapy in patients with relapsed and refractory MM, the median PFS was 7 months [4], whereas in pivotal trials for the approval of lenalidomide in combination with dexamethasone in the same group of patients, the median time to progression was approximately 11 months [5,6]. A recent prospective, randomized, phase III study showed that a triplet combination of bortezomib, thalidomide, and dexamethasone achieved superior results compared with thalidomideedexamethasone alone in patients relapsing after ASCT, with a median time to progression of 19.5 versus 13.8 months, respectively [7]. This study suggested that combinations consisting of both an immunomodulatory drug and a proteasome inhibitor are a valuable option at the time of relapse. However, when a frozen graft is available, it is also possible to repeat high-dose therapy in patients who previously responded to the frontline application of high-dose melphalan and ASCT [8]. Over time, many reports have demonstrated the feasibility of this salvage strategy [9-19]. Most data are available from retrospective studies and are based on single-center experiences with small numbers of selected patients. In this setting, PFS has been shown to range from 7 to 22 months, and treatment-related mortality was acceptable, ranging from 0% to 8%. Various prognostic factors for prolonged PFS have been described, such as the duration of response to the first high-dose therapy [9,10,13-16,19] or the number of lines of therapy before salvage ASCT [9,10]. Here, we report the results of a retrospective analysis of salvage ASCT conducted in three French centers. Our goals were to identify prognostic factors for prolonged PFS and OS. Financial disclosure: See Acknowledgments on page 449. * Correspondence and reprint requests: Philippe Moreau, MD, Hematology Department, University Hospital Hôtel-Dieu, Place Ricordeau, Nantes, France. address: philippe.moreau@chu-nantes.fr (P. Moreau). y E. Lemieux and C. Hulin equally contributed to this work /$ e see front matter Ó 2013 American Society for Blood and Marrow Transplantation. METHODS In this retrospective analysis, all consecutive patients treated between 1995 and 2009 at centers of Nancy, Dijon, and Nantes with high-dose therapy and ASCT as part of salvage therapy after a frontline single or tandem ASCT and a subsequent relapse were included. To have a reliable

2 446 E. Lemieux et al. / Biol Blood Marrow Transplant 19 (2013) 445e449 follow-up time, patients who received salvage ASCT after January 1, 2010, were not included in the present analysis. The choice of salvage ASCT instead of other options was left to the treating physician and was also dependent on stem cell availability. In addition, patients had to present with adequate cardiac, lung, liver, or renal function, according to each center s policy. Response Criteria Response and progression were defined according to the International Myeloma Working Group criteria [20]. Briefly, a complete response was defined as negative immunofixation of serum and urine, disappearance of soft tissue plasmacytoma, and 5% plasma cells in the bone marrow. Very good partial response (VGPR) was defined as serum and urine M-protein detectable only by immunofixation or as a 90% or greater reduction in serum M-protein plus a urine M-protein level of <100 mg per 24 hours. Partial response (PR) was defined as a reduction in serum M-protein of at least 50% and by a reduction of at least 90% or an absolute value of <200 mg per 24 hours in urine M-protein. Stable disease was defined as not meeting any response criteria, and progressive disease was defined as a confirmed increase of 25% of M-protein from baseline. Relapse was defined as the reappearance of serum or urine M-protein or the development of new bone lesions, plasmacytoma, or hypercalcemia. Response post-asct was assessed at a maximum 100 days post transplantation, and patients were followed approximately every 3 months thereafter. Statistical Analysis PFS1 was defined from the date of the first ASCT to the date of first relapse or progression. PFS2 was defined from the date of salvage ASCT to the date of subsequent relapse or progression. OS rates were estimated from the date of diagnosis or from the date of relapse to the date of death or to the date of the last follow-up for patients who were still alive. Kaplan-Meier curves for PFS and OS were plotted and compared using a log-rank test. Predictive factors were determined by univariate analysis using Kaplan- Meier curves and the log-rank test. Only predictive factors with a significant result (P <.05) in univariate analysis entered multivariate analysis, using Cox regression. Statistical analysis was performed using SAS 9.3 (SAS Institute, Cary, NC). RESULTS From January 1995 to December 2009, 81 patients were treated with salvage ASCT. Patient characteristics at the time of diagnosis of symptomatic MM are shown in Table 1. The median time from diagnosis to the first ASCT was 4 months. Thirty-six percent of patients received tandem ASCT, 95% responded to high-dose therapy, and 58% received some form of maintenance therapy, the median duration of which was 16 months (range, 1 to 64). Patient characteristics at the time of salvage ASCT are listed in Table 2. The median time between the first and the salvage ASCT was 47 months (range, 13 to 168). Ninety-five percent of patients received induction therapy before salvage ASCT, which consisted of novel agentebased regimen in half, and four patients proceeded to ASCT without any salvage chemotherapy. Only 26 patients (32%) received more than 2 lines of therapy before salvage ASCT. At the time of salvage ASCT, 67 patients (83%) had achieved at least a PR to induction therapy, 10 (12%) had not responded to induction, and 4 were in an untreated relapse. Fifty-eight of 81 patients (72%) received stem cells that had been harvested before the first ASCT. For 23 patients (28%), stem cells were harvested after the first relapse using granulocyte colony-stimulating factor alone (13 patients), cyclophosphamide þ granulocyte colony-stimulating factor (6 patients), or plerixafor þ granulocyte colony-stimulating factor (4 patients). After salvage ASCT, 75 patients (93%) achieved at least a PR, including 67% VGPR, and no toxic death was reported. Sixteen patients (20%) received consolidation therapy, whereas 30 (37%) received some form of maintenance therapy after salvage ASCT. Table 1 Patient Characteristics at Diagnosis and First High-Dose Therapy Step Variable (N ¼ 81) Median age at diagnosis (range) 55 (30-67) Male 47 (58%) Female 34 (42%) Durie-Salmon stage I 4 (5%) II 9 (11%) III 68 (84%) International Staging System 1 40 (49%) 2 22 (27%) 3 14 (17%) Missing data 5 (7%) Isotype IgG 53 (65%) IgA 10 (12%) Light chain 18 (23%) Induction regimen before first ASCT VAD 69 (85%) VMCP-VBAP 4 (5%) Bortezomib-dexamethasone 8 (10%) Conditioning regimen before first ASCT Melphalan 200 mg/m 2 40 (49%) Melphalan 140 mg/m 2 23 (28%) Melphalan 140 þ 8 Gy total body irradiation 12 (15%) Other 6 (7%) Tandem ASCT 29 (36%) Response after first high-dose therapy VGPR 58 (72%) PR 19 (23%) SD 4 (5%) Maintenance therapy after first high-dose therapy Interferon-a 24 (30%) Thalidomide 13 (16%) Lenalidomide 6 (7%) Other 4 (5%) None 34 (42%) VAD indicates vincristine, adriamycin, dexamethasone; VMCP-VBAP, vincristine, melphalan, cyclophosphamide, prednisone-vincristine, carmustine, doxorubicin, prednisone; SD, stable disease. Survival and Prognostic Factors The median follow-up time for living patients was 7 years (range, 2.1 to 16.6). The median OS was 10 years from diagnosis and 4 years from salvage ASCT (Figure 1). The median PFS1 was 40 months (range, 10 to 152), and the median PFS2 was 18 months (range, 2 to 64) (Figure 1). The duration of the second response was found to be related to PFS1: The median PFS2 was 26.4 months in patients experiencing their first relapse more than 40 months after the first ASCT versus 14 months in patients relapsing within the first 40 months after their first ASCT, P ¼.001 (Figure 2). A cut-off value of 24 months for relapse after the first ASCT was also found to significantly affect PFS2, with a duration of second response of 9 versus 18 months (P ¼.0096) for patients relapsing within 24 months versus those with a relapse more than 24 months after the first ASCT. The analysis was not performed for a shorter duration of first response due to the small number of patients relapsing within 18 months after their first ASCT. In addition, the duration of response after the first ASCT also affected OS. The median OS rate from salvage therapy was longer in patients relapsing 24 or 40 months after their first ASCT versus others (median 7.2 and 7.3 versus 2.4 and 3.4 years, respectively; P <.05). The duration of response after salvage ASCT was also significantly affected by the use of maintenance therapy (Figure 3). Results of the univariate analysis of prognostic factors are presented in Table 3. In the multivariate analysis,

3 E. Lemieux et al. / Biol Blood Marrow Transplant 19 (2013) 445e Table 2 Salvage ASCT Variable (N ¼ 81) Median age at the time of salvage ASCT (range) 58 (35-71) Novel induction regimen before salvage ASCT VAD 23 (29%) Bortezomib-dexamethasone or lenalidomidedexamethasone 26 (32%) or thalidomide-dexamethasone VTD or VRD 10 (12%) Others 18 (22%) None 4 (5%) Conditioning regimen before salvage ASCT Melphalan 220 mg/m 2 12 (15%) Melphalan 200 mg/m 2 45 (56%) Melphalan 140 mg/m 2 9 (11%) Melphalan þ busulphan 2 (2%) Others 13 (16%) Response after salvage ASCT VGPR 54 (67%) PR 21 (26%) SD 5 (6%) PD 1 (1%) Transplantation-related death 0 Consolidation therapy after salvage ASCT Bortezomib-dexamethasone 6 (7%) VTD 2 (3%) VRD 4 (5%) Lenalidomide-dexamethasone 4 (5%) None 65 (80%) Maintenance therapy after salvage ASCT Thalidomide 11 (14%) Lenalidomide 12 (15%) Bortezomib 3 (4%) Other 4 (5%) None 51 (63%) VAD indicates vincristine, adriamycin, dexamethasone; VTD, bortezomibthalidomide-dexamethasone; VRD, bortezomib-lenalidomide-dexamethasone; SD, stable disease; PD, progressive disease. three independent factors unfavorably affected PFS: a short duration of response to the first ASCT, a response less than a VGPR after salvage therapy, and no maintenance treatment after salvage ASCT. Age over 60 years and a short duration of response after the first ASCT were the two factors adversely affecting OS from the time of diagnosis and OS from the time of salvage ASCT (Table 4). DISCUSSION Currently, there is no broadly accepted standard treatment for patients with relapsed/refractory MM [21]. For the Figure 2. Progression-free survival rates after salvage ASCT according to the duration of response after the first ASCT (<40 or >40 months). selection of an appropriate treatment strategy at this stage, both disease-related and patient-related factors and, importantly, the type of previous therapy need to be considered [21-25]. Disease-related factors include the quality and duration of response to previous therapies and the aggressiveness of the relapse, whereas patient-related factors comprise pre-existing toxicities, comorbid conditions, quality of life, age, and performance status [21-25]. Regarding previous therapies, it is important to take into account if the patient has been exposed to alkylators or to the novel agents, immunomodulatory drugs and proteasome inhibitors, and if this was alone or in combination, to define the best strategy [21-26]. Intensive therapy can always be considered at this stage [21]. Although allogeneic transplantation shows limited clinical benefit for the treatment of patients with relapsed/ refractory MM [27], available data suggest that a second autologous transplantation may be beneficial and well tolerated for some patients in this setting [21-23]. The overall response rates in studies range from 55% to 69%, with a 100- day mortality rate <10% [8-19]. However, the small sample size used in these studies complicates the identification of the ideal candidate for this treatment approach. Most reports suggest that the duration of the first response to ASCT is the major prognostic factor [8-19]. In the current retrospective study, we confirm that salvage ASCT at the time of relapse is a valuable and feasible option. Response rates were high, with more than 90% of Figure 1. Progression-free and overall survival rates. Figure 3. Progression-free survival rates after salvage ASCT according to maintenance therapy.

4 448 E. Lemieux et al. / Biol Blood Marrow Transplant 19 (2013) 445e449 Table 3 Univariate Analysis of Variables Unfavorably Affecting Progression-Free and Overall Survival Rates Variable (P <.05) HR 95% CI P Value Progression-free survival after salvage ASCT Duration of response after first ASCT < 24 mo 2.40 [1.21, 4.76].01 Duration of response after first ASCT < 40 mo 2.78 [1.62, 4.77].0002 Response after salvage ASCT < VGPR 2.48 [1.42, 4.10].001 No maintenance therapy after salvage ASCT 3.32 [1.76, 6.29].0002 Overall survival from diagnosis Age > 60 y 5.09 [2.33, 11.10] <.0001 b 2 -microglobulin at diagnosis > 3.5 mg/l 2.21 [1.12, 4.35].02 Duration of response after first ASCT < 24 mo 6.85 [3.27, 14.86] <.0001 Duration of response after first ASCT < 40 mo 7.08 [3.35, 14.99] <.0001 Response after first ASCT < VGPR 2.80 [1.48, 5.28] Response after salvage ASCT < VGPR 3.81 [2.00, 7.23] <.0001 No maintenance therapy after salvage ASCT 2.83 [1.23, 6.49].01 Overall survival from salvage ASCT Age > 60 y 2.89 [1.43, 5.86].003 Duration of response after first ASCT < 24 mo 3.65 [1.77, 7.53].0004 Duration of response after first ASCT < 40 mo 3.47 [1.68, 7.18].0008 Response after first ASCT < VGPR 2.25 [ ].01 Response after salvage ASCT < VGPR 2.76 [1.43, 5.31].002 HR indicates hazard ratio; CI, confidence interval. patients achieving at least a PR, with no transplantationrelated mortality. Our results thereby confirm those reported by various groups [9-19]. In addition, similar to what has previously been described, we show that the duration of response to the first ASCT is the major prognostic factor for both PFS and OS. In our series, a duration of response of at least 24 months to the first intensive therapy was associated with a longer PFS and OS. This cut-off value of 24 months was also described in a series of 81 patients treated at the Princess Margaret Hospital, Toronto, Ontario, Canada [16]. Different cut-off values, ranging from 12 to 24 months, have already been proposed by several investigators [9,15,19]. Interestingly, we found that a response of less than VGPR after salvage ASCT was an independent adverse prognostic factor for PFS. It is only the second time this factor, which is a known prognostic factor in the frontline ASCT setting [3], has been described to be important in the context of salvage ASCT [16]. Of note, we were able to analyze the impact of maintenance therapy after salvage ASCT and showed for the first time that maintenance might significantly prolong the duration of response. The role of maintenance in the frontline setting is a matter of controversy [28], despite the overwhelming strong evidence of an improvement in PFS when immunomodulatory drugs are administered after upfront ASCT [29,30]. Our findings will feed the debate on the role of maintenance in the setting of salvage ASCT. Of note in our analysis is that some patients received an autograft that had been cryopreserved and stored for 10 years before the salvage ASCT [8]. There are a number of limitations to our study. First, it was not an intent-to-treat analysis, and we lack precise data on how many patients were excluded from salvage ASCT because of comorbidity, an insufficient amount of stem cells, or progressive and/or refractory disease. This selection bias is the most important shortcoming. Second, the study is related to the long period of accrual, which explains the heterogeneity in the treatment received by the patients, both as part of frontline therapy and at the time of relapse. Clearly, the role of salvage ASCT has to be re-examined in the context of novel agents. Moreover, we collected cytogenetic data in only some patients, and salvage therapies have to be evaluated, if possible, with this information available. Nevertheless, our data show that salvage ASCT is a feasible option that should be routinely considered at the time of relapse for patients with a response duration of more than 2 years to frontline high-dose therapy. The feasibility of salvage ASCT might also be improved in the future with novel strategies of stem cell collection, such as the use of plerixafor, which allows the collection of stem cells in patients previously exposed to high-dose therapy [31]. Table 4 Multivariate Cox Regression Analysis of Variables Unfavorably Affecting Progression-Free and Overall Survival Rates Variable (P <.05) HR 95% CI P Value Progression-free survival after salvage ASCT Duration of response after first ASCT < 24 mo 2.25 [1.02, 4.98].04 Duration of response after first ASCT < 40 mo 2.46 [1.40, 4.32].001 Response after salvage ASCT < VGPR 1.97 [1.02, 3.80].04 No maintenance therapy after salvage ASCT 3.40 [1.72, 6.69].0004 Overall survival from diagnosis Age > 60 y 4.00 [1.50, 10.71].006 Duration of response after first ASCT < 24 mo [3.98, 55.70] <.0001 Duration of response after first ASCT < 40 mo 4.67 [2.04, 10.70].0003 Overall survival from salvage ASCT Age > 60 y 3.62 [1.39, 9.42].008 Duration of response after first ASCT < 24 mo 8.25 [2.93, 23.22] <.0001 Duration of response after first ASCT < 40 mo 4.45 [1.93, 10.24].0004 HR indicates hazard ratio; CI, confidence interval.

5 E. Lemieux et al. / Biol Blood Marrow Transplant 19 (2013) 445e ACKNOWLEDGMENTS Financial disclosure: The authors have nothing to disclose. REFERENCES 1. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med. 1996;3335: Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003;348: Moreau P, Avet-Loiseau H, Harousseau JL, Attal M. Current trends in autologous stem cell transplantation for myeloma in the era of novel therapies. J Clin Oncol. 2011;29: Richardson PG, Sonneveld P, Schuster M, et al. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood. 2007;110: Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. 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