Autologous Retransplantation for Patients With Recurrent Multiple Myeloma

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1 Autologous Retransplantation for Patients With Recurrent Multiple Myeloma A Single-Center Experience with 200 Patients Leopold Sellner, MD 1 ; Christiane Heiss 2 ; Axel Benner 2 ; Marc S. Raab, MD 1 ; Jens Hillengass, MD 1 ; Dirk Hose, MD 3 ; Nicola Lehners, MD 1 ; Gerlinde Egerer, MD 1 ; Anthony D. Ho, MD 1 ; Hartmut Goldschmidt, MD 3 ; and Kai Neben, MD 1 BACKGROUND: Therapeutic options for patients with recurrent multiple myeloma after autologous stem cell transplantation (ASCT) include novel agents, conventional chemotherapy, or salvage ASCT with no standard of care. METHODS: A total of 200 patients with multiple myeloma who developed disease recurrence after treatment with upfront ASCT and received an autologous retransplantation as salvage therapy at the study center over a period of 15 years were retrospectively reviewed. The objective of the current study was to evaluate the role of salvage ASCT in terms of efficacy, particularly taking into account the impact of novel agents. RESULTS: The median progression-free survival (PFS) and overall survival after salvage ASCT were 15.2 months and 42.3 months, respectively. The overall response rate (a partial response or greater) was 80.4% at day 100, excluding 6 patients who died before assessment. Factors associated with improved PFS and overall survival after salvage ASCT included an initial PFS of > 18 months after upfront ASCT, bortezomib-containing or lenalidomide-containing therapies for reinduction, response to reinduction, and an International Staging System stage of I before salvage ASCT. CONCLUSIONS: Salvage ASCT is capable of achieving sustained disease control in patients with multiple myeloma. The use of lenalidomide and bortezomib for reinduction has improved the results after salvage ASCT, suggesting that novel agents and salvage ASCT are complementary rather than alternative treatment approaches. Cancer 2013;000: VC 2013 American Cancer Society. KEYWORDS: multiple myeloma; salvage therapy; autologous stem cell transplantation; lenalidomide; bortezomib. INTRODUCTION High-dose therapy (HDT) followed by autologous hematopoietic stem cell transplantation (ASCT) is recommended for patients with active multiple myeloma who are aged < 65 to 70 years and do not have serious coexisting illnesses. 1 The Intergroupe Francophone du Myelome and the British Medical Research Council conducted 2 randomized trials demonstrating the superiority of this approach compared with conventional chemotherapy, and provided evidence of a > 10-year survival in a subset of patients. 2,3 In recent years, the introduction of new drugs such as thalidomide, bortezomib, and lenalidomide has significantly improved response rates, progression-free survival (PFS), and overall survival (OS). Before 1996, the median OS among patients who required therapy was approximately 3 years, 4 whereas in the era of new agents and ASCT, the median OS after ASCT is close to 8 years. 5 With regard to first-line therapy, these data suggest that comprehensive treatment protocols combining novel agents with ASCT are complementary rather than alternative treatment approaches. Despite the better outcome noted with HDT and ASCT compared with conventional-dose treatment, most patients eventually develop disease recurrence. Subsequent treatment options for patients with recurrent or refractory multiple myeloma include salvage therapies with novel agents and/or conventional chemotherapy. In addition, HDT followed by ASCT as consolidation therapy is a clinical option for patients who are eligible for stem cell transplantation In the absence of data from randomized controlled trials, the British Society of Blood and Marrow Transplantation performed a case-control study that demonstrated that the OS of patients Corresponding author: Kai Neben, MD, Department of Internal Medicine V, University of Heidelberg, Im Neuenheimer Feld 410, Heidelberg, Germany; Fax: (011) ; kai.neben@med.uni-heidelberg.de 1 Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany; 2 Department of Biostatistics, German Cancer Research Center, Heidelberg, Germany; 3 Department of Internal Medicine V, National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany. We thank Katrin Heimlich, Maria D orner, and Hildegard Beth auser for technical assistance in the enrichment of CD138-positive plasma cells and Michaela Brough, Stephanie Pschowski-Zuck, and Desiree Kirn for performing interphase fluorescence in situ hybridization analysis. DOI: /cncr.28104, Received: October 31, 2012; Revised: February 15, 2013; Accepted: March 7, 2013, Published online Month 00, 2013 in Wiley Online Library (wileyonlinelibrary.com) Cancer Month 00,

2 after salvage ASCT is superior compared with that for patients receiving conventional chemotherapy (32% vs 22% at 4 years; P 5.002). 11 The best outcome was observed in patients whose initial PFS was > 24 months after upfront ASCT, because these patients had a subsequent PFS lasting > 1 year and an OS of nearly 6 years. 14 However, the majority of the previous studies were limited by the low numbers of patients analyzed or were performed before the introduction of novel agents such as lenalidomide and bortezomib. Thus, the objective of the current study was to evaluate the role of salvage ASCT in terms of efficacy, particularly taking into account the impact of novel agents in a large cohort of 200 patients with multiple myeloma. MATERIALS AND METHODS Patient Cohort Between June 1992 and November 2010, a total of 1262 patients with multiple myeloma received HDT followed by ASCT at the Hematology Department of the University Hospital Heidelberg in Heidelberg, Germany. Herein, we retrospectively reviewed all patients with multiple myeloma who developed disease recurrence after initial ASCT and received HDT with melphalan followed by ASCT as salvage therapy at our center from May 1995 to November Patients were treated with single (126 patients) or tandem (74 patients) ASCT as part of their initial treatment. Patients who developed disease recurrence after the upfront ASCT were considered for salvage ASCT if their organ function was adequate, they exhibited a good performance status at the time of disease recurrence, they had sufficient numbers of CD34-positive cells available, and they agreed to salvage ASCT. HDT was performed with melphalan in all patients. Although 177 patients received the full dose of melphalan (200 mg/m 2 ), the dose was reduced to 150 mg/m 2 in 2 patients, 140 mg/m 2 in 1 patient, and 100 mg/m 2 in 14 patients because of abnormal kidney function (creatinine clearance < 40 ml/min) or age > 70 years. Because of the long follow-up of the study, no information concerning the melphalan dosage administered was available for 6 patients. At least CD34-positive peripheral blood stem cells/ kg body weight were used for ASCT. The ethical review board of the University of Heidelberg approved this retrospective study and informed consent was obtained from all patients. Definitions and Response Assessment A transplant was defined as salvage ASCT if the patient had developed disease recurrence after upfront ASCT and underwent reinduction therapy followed by salvage ASCT after evidence of disease progression, regardless of the number of lines of treatment administered after upfront ASCT. Induction therapy, stem cell mobilization therapy, and HDT followed by ASCT were counted together as a single line of treatment. Interphase fluorescence in situ hybridization (FISH) analysis was performed in a subset of patients anytime before salvage ASCT and accomplished on CD138-purified plasma cells as previously described 15 using probes for chromosomes 1q21 and 17p13, as for the translocation t(4;14)(p16.3;q32.3). The response to treatment was assessed according to the European Group for Blood and Marrow Transplantation criteria for complete response, partial response (PR), minimal response, stable disease, and progressive disease. 15 These criteria were complemented by the criteria of the International Myeloma Working Group for the definition of a very good PR. 16 Response was assessed on day 100 (range, 60 days-150 days) after salvage ASCT. After day 100 assessments, patients were seen in the clinic at least every 2 to 3 months. Statistical Analysis Differences in continuous variables between the groups were compared using the Mann-Whitney U test or Kruskal-Wallis test. PFS was defined as the time from the date of salvage ASCT to disease progression or death, whereas OS was defined as the time from the date of ASCT to the date of death from any cause. The initial PFS after upfront ASCT was calculated from the date of stem cell infusion of the first ASCT to the time of disease progression. Patients still alive at the time of last follow-up were censored at that date. Estimation of PFS and OS distribution was performed by the Kaplan-Meier method. For comparisons of OS and PFS curves, the log-rank test was used. Univariate and multivariate Cox proportional hazards regression analysis was performed to evaluate the prognostic impact on PFS and OS. The results were illustrated presenting hazards ratios including 95% confidence intervals (95% CIs). For the multivariate analysis, multiple imputations using predictive mean matching were performed. P values <.05 were considered statistically significant. All statistical analyses were performed within the R statistical software environment (R version ) using the R package rms (version 3.3-0; R Foundation, Vienna, Austria). 2 Cancer Month 00, 2013

3 ASCT as Salvage Therapy in MM/Sellner et al TABLE 1. Characteristics of 200 Patients With Multiple Myeloma Characteristic No. of Patients Frequency Median (Range) Male sex % Paraprotein type (n5200) IgG % IgA 51 26% Bence Jones 27 14% Other 13 7% ISS stage at diagnosis (n5154) I 92 60% II 40 26% III 22 14% Induction regimen Vincristine/doxorubicin/dexamethasone % Thalidomide/doxorubicin/dexamethasone 9 5% Bortezomib/doxorubicin/dexamethasone 6 3% Lenalidomide-containing 0 0 Others 51 26% Tandem ASCT as part of initial treatment 74 37% Maintenance therapy after upfront ASCT (n5196) None 84 43% a-interferon 88 45% Thalidomide or bortezomib 24 12% No. of regimens prior to salvage ASCT 2 (1-8) Reinduction regimen Bortezomib-containing 14 7% Lenalidomide-containing 44 22% Thalidomide-containing 76 38% CHT/dexamethasone-based 66 33% Age at salvage ASCT, y 60 (29-72) ISS stage at salvage ASCT (n5186) I % II 36 19% III 21 11% LDH level at salvage ASCT (n5195; ULN5248 U/L) 181 ( ) Maintenance therapy after salvage ASCT (n5195) None % Thalidomide 59 30% a-interferon 7 4% Lenalidomide 3 2% Prednisone 3 2% Bortezomib 1 1% RESULTS Patients Between May 1995 and November 2010, 200 patients received salvage ASCT for recurrent multiple myeloma at the study institution. Clinical characteristics are shown in Table 1. The median follow-up for all patients since salvage ASCT was 57.1 months (95% CI, 52.7 months-63.6 months). During follow-up, 111 deaths occurred. At the time of salvage ASCT, the median age of the patients was 60 years (range, 29 years-72 years); 20% of the patients were aged > 65 years. Treatment Algorithm and Patient Outcome After upfront ASCT, the initial median PFS was 64.6 months (95% CI, 56.8 months-74.3 months), whereas the median OS was 87.3 months (95% CI, 81.4 months months). Within 6 months after the first ASCT, 74 patients were consolidated with a second HDT with melphalan followed by ASCT as part of the initial treatment. All patients received reinduction therapy before salvage ASCT. The 100-day mortality rate after salvage ASCT was 3% (6 patients). The presumed cause of death in these 6 patients was a severe infection within 95 days after ASCT; however, 3 of these individuals had demonstrated signs of early disease progression after salvage ASCT. Maintenance therapy was initiated in 73 patients after salvage ASCT; 59 patients received thalidomide or a-interferon plus thalidomide, 3 patients received prednisone, 7 patients received a-interferon, 3 patients received lenalidomide, and 1 patient received bortezomib. On day 100 after ASCT (n patients), the response assessment revealed a complete response, very good PR, PR, minimal response, stable disease, and progressive disease in 25 (12.9%), 17 (8.8%), 114 (58.7%), 19 (9.8%), 8 (4.1%), Cancer Month 00,

4 TABLE 2. Univariate Cox Proportional Hazards Regression of Possible Prognostic Factors PFS OS Variable No. of Patients HR 95% CI P HR 95% CI P Age at recurrence-asct.16 (10-y increment) No. of regimens prior to recurrence-asct Response to reinduction PR <PR Remission duration after first ASCT >18 mo mo mo Reinduction Thalidomide or chemotherapy-based Lenalidomide- or bortezomib-based LDH level at salvage ASCT (increment of 100 U/L) Paraprotein type IgG Bence Jones IgA Other ISS stage prior to salvage ASCT.10 <.001 I II III Abbreviations: 95% CI, 95% confidence interval; ASCT, autologous stem cell transplantation; HR, hazards ratio; Ig, immunoglobulin; ISS, International Staging System; LDH, lactate dehydrogenase; OS, overall survival; PFS, progression-free survival; PR, partial response. and 11 (5.7%) patients, respectively. The overall response rate (PR) was 80.4% at day 100, excluding the 6 patients who died before assessment. After salvage ASCT, the median PFS was 15.2 months (95% CI, 13.3 months months), whereas the median OS was 42.3 months (95% CI, 33.5 months-49.7 months). Impact of Prognostic Factors on PFS and OS Prognostic variables before salvage ASCT examined for their impact on PFS and OS in univariate Cox regression models that included age; gender; multiple myeloma isotype; number of upfront transplantations (single vs tandem ASCT); number of prior regimens; exposure to novel agents such as thalidomide, lenalidomide, and bortezomib; use of maintenance therapy after upfront and salvage ASCT; initial PFS after upfront ASCT; response to upfront ASCT as to reinduction before salvage ASCT; ISS stage at diagnosis and before salvage ASCT; and lactate dehydrogenase levels at the time of diagnosis and before salvage ASCT. On univariate analysis (Table 2) (Fig. 1), the most important factors found to be predictive for PFS and OS were initial PFS after upfront ASCT ( 12 months vs 13 months-18 months vs > 18 months; P 5.24 and P 5.001, respectively), ISS stage before salvage ASCT (I vs II vs III; P 5.10 and P <.001, respectively), achievement of at least a PR after reinduction (yes vs no; P 5.02 and P 5.17, respectively), and the use of bortezomib or lenalidomide for reinduction before salvage ASCT (yes vs no; P 5.25 and P<.001, respectively). For the entire group of patients, a lack of response to reinduction therapy, short initial PFS time after upfront ASCT, and non-immunoglobulin G isotype were identified as independent predictors for adverse PFS on multivariate analysis (Table 3). In addition, a short initial PFS time after upfront ASCT, no use of bortezomib or lenalidomide for reinduction, elevated lactate dehydrogenase levels at salvage ASCT, and an ISS stage of II or III before salvage ASCT were found to be independent predictors for OS. Prognostic Stratification According to Response Time and ISS Stage Based on the results of the univariate and multivariate analyses, we analyzed whether combining the ISS stage before salvage ASCT with information regarding the initial PFS after upfront ASCT could improve the 4 Cancer Month 00, 2013

5 ASCT as Salvage Therapy in MM/Sellner et al Figure 1. Prognostic factors that have demonstrated an impact on progression-free survival (PFS) and overall survival (OS) after salvage autologous stem cell transplantation (ASCT) are shown. Kaplan-Meier analysis is shown for (A and B) International Staging System (ISS) stage before salvage ASCT, (C and D) initial PFS after upfront ASCT, (E and F) response to reinduction, and (G and H) bortezomib (Borte)-containing or lenalidomide (Lena)-containing therapies for reinduction. Thal indicates thalidomide; PR, partial response. Cancer Month 00,

6 TABLE 3. Multivariate Cox Proportional Hazards Regression of Possibley Prognostic Factors PFS OS Variable HR 95% CI P HR 95% CI P Age at recurrence-asct (10-y increment) No. of regimens prior to recurrence-asct (3 vs 1-2) Response to reinduction (<PR vs PR) Remission duration after first ASCT.04 < mo vs >18 mo mo vs >18 mo Reinduction with lenalidomide or bortezomib vs thalidomide or chemotherapy LDH level at salvage ASCT (increment of 100 U/L) Paraprotein type Bence Jones vs IgG IgA vs IgG Other vs IgG ISS stage prior to salvage ASCT II vs I III vs I Abbreviations: 95% CI, 95% confidence interval; ASCT, autologous stem cell transplantation; HR, hazards ratio; Ig, immunoglobulin; ISS, International Staging System; LDH, lactate dehydrogenase; OS, overall survival; PFS, progression-free survival; PR, partial response. prognostic value with regard to patients OS (Fig. 2). A combination of the initial PFS after upfront ASCT ( 18 months vs > 18 months) with the ISS stage (I vs II/III) allowed patients to be stratified into 3 distinct groups: those at low risk (> 18 months and ISS stage I), those at high risk ( 18 months and ISS stage II/III), and those at intermediate risk (the remaining patients). The majority of the patients belonged to the low-risk (51.6%) and intermediate-risk (39.8%) groups, whereas only 8.6% were allocated to the high-risk group. The median OS decreased from 58.5 months in the low-risk group to 33.9 months and 13.5 months in the intermediate-risk and high-risk groups, respectively (P <.0001). With regard to PFS, the prognostic stratification according to response time and ISS stage was found to be of only marginal significance (P 5.04). Correlation of Chromosomal Aberrations With Patient Outcome We analyzed the prognostic impact of chromosomal aberrations on PFS and OS for a subgroup of patients with available cytogenetic data. Interphase FISH analysis of CD138-enriched plasma cells was only performed on a regular basis after January 2004; therefore, this data point was not available for all patients. Cytogenetic analysis revealed gains of chromosomes 1q21 in 41 of 71 patients (58%) and deletions of chromosome 17p13 in 14 of 80 patients (18%). Furthermore, the immunoglobulin H translocation t(4;14) was observed in 9 of 80 patients (11%). The presence of del(17p13), t(4;14), and 11q21 was associated with adverse impact on both PFS and OS. However, due to the low numbers of patients, this effect did not reach statistical significance when each subgroup was analyzed individually. Therefore, patient status was classified as either favorable or adverse according to Avet-Loiseau et al 19 : adverse FISH was defined as the cytogenetic abnormalities 11q21, t(4;14), and del(17p13), whereas favorable FISH was defined by the absence of these cytogenetic abnormalities (Fig. 3). The median PFS for patients with adverse FISH was 13.2 months versus 25.6 months for those with favorable FISH (P 5.03); the 4-year OS rate was 52% versus 71%, respectively (P 5.09). DISCUSSION To the best of our knowledge, the current study is one of the largest studies published to date describing the impact of salvage ASCT in patients with multiple myeloma in a series of 200 patients. An overall response rate (PR) was obtained in 80.4% of these patients. When the response to reinduction was compared with the response after salvage ASCT at day 100, the remission status was improved in 72 patients, whereas 4 patients were diagnosed with progressive disease. It is interesting to note that only a small number of patients received novel agents as part of their primary therapy, which most likely explains the high response rates to reinduction treatment and salvage ASCT. PFS and OS were 15.2 months and 42.3 months, respectively, after salvage ASCT. This compares favorably with previously published smaller studies in this setting, although those studies are very heterogeneous in terms of patient selection, the agents used for reinduction, the type 6 Cancer Month 00, 2013

7 ASCT as Salvage Therapy in MM/Sellner et al Figure 2. Combining information regarding initial progression-free survival (PFS) after upfront autologous stem cell transplantation (ASCT) with the International Staging System (ISS) stage allows for the prediction of overall survival (OS) after salvage ASCT. According to the initial PFS ( 18 months vs > 18 months) and ISS stage (stage I vs stage II/III), the cohort could be stratified into 3 distinct groups: a group with a low risk (> 18 months and ISS stage I), a group with a high risk ( 18 months and ISS stage II/III), and a group with an intermediate risk (all remaining patients). HR indicates hazards ratio. of conditioning regimen, and the application of maintenance therapy. In the current study, all patients received reinduction therapy. In addition, melphalan was used as HDT in all patients. We found salvage ASCT to be a feasible and safe treatment option in patients with recurrent multiple myeloma, as demonstrated by a 100-day mortality rate of 3%. However, 2 studies reported a 100-day mortality rate of 8%, 8,11 suggesting that treatment-related mortality with salvage ASCT might be greater than that after an upfront transplant. 1 This may be a consequence of a presumably poorer performance status and higher age when patients are treated with salvage ASCT. To the best of our knowledge, randomized controlled studies evaluating the role of salvage ASCT or systematic outcome analyses including cytogenetic data in the setting of recurrent multiple myeloma are missing. Thus, there is a lack of clear guidance and criteria for the selection of patients who may best benefit from this approach. In general, the results of the current study demonstrate that it is easier to predict OS than PFS after salvage ASCT. The reason for this might be that the Figure 3. Impact of cytogenetic aberrations associated with poor prognosis (ie, t(4;14), del(17p13), 11q21) on (A) progression-free survival (PFS) and (B) overall survival (OS). Patients with multiple myeloma were stratified by the presence or absence of high-risk cytogenetic aberrations. ASCT indicates autologous stem cell transplantation. majority of the prognostic factors identified to date are not treatment specific for salvage ASCT and reflect the natural course of disease. Patients with favorable prognostic factors before salvage ASCT (ie, low ISS stages and long PFS times after upfront ASCT) might also have a good chance of responding to additional lines of treatment, in particular in the area of novel drugs. To date, the initial PFS after upfront ASCT appears to be the most robust selection criteria for patients before salvage ASCT. 9,11,12,14 In the current study, patients whose initial PFS after upfront ASCT was < 12 months reached a median PFS and OS of 7.2 months and 11.6 months, respectively, after salvage ASCT, whereas a median PFS and OS Cancer Month 00,

8 of 15.8 months and 49.2 months, respectively, were achieved if the initial PFS was > 18 months. It is known that the ISS stage reflects tumor burden and is correlated with kidney function. 18 Because a substantial percentage of patients with multiple myeloma are transferred to transplantation centers with incomplete information regarding their prognostic factors at diagnosis, we assessed the ISS stage obtained at the time of salvage ASCT, which was available in 186 of 200 patients (93%). Patients with an ISS stage of I achieved a nearly doubled median OS compared with patients with an ISS stage of II or III (56.3 months vs 27.6 months vs 18.1 months, respectively; P 5.004). Because our statistical analyses revealed that initial PFS after upfront ASCT and ISS stage before salvage ASCT were the 2 most important factors for OS, we combined both variables to improve the prognostic value with regard to patients outcome. The prognostic stratification developed based on initial PFS and ISS stage allows for the identification of patients who might benefit the most by undergoing salvage ASCT. Although the results obtained by this model appear to be very robust in the current study, they must be confirmed in independent patient cohorts. It is interesting to note that the results of the current study confirm the prognostic impact of chromosomal aberrations in the context of salvage ASCT. Because 2 recent studies demonstrated that t(4;14), del(17p13), and 11q21 are most likely the most relevant chromosomal aberrations for predicting outcome at upfront ASCT, 15,19 we used these abnormalities to define patients with favorable and adverse cytogenetic risk. We found that patients with adverse cytogenetic factors had a significantly shorter PFS, whereas the results regarding OS did not reach statistical significance due to only few events taking place to date, suggesting that a longer follow-up time is required. There are some general limitations of retrospective studies in analyzing the role of salvage ASCT in patients with multiple myeloma. We and other authors were not able to perform an intent-to-treat analysis (ie, it is not clear how many patients failed to mobilize sufficient stem cells and therefore could not be considered for salvage transplant). The patients in the current study had an excellent median PFS of 64.6 months after upfront ASCT, suggesting a selection bias toward young and fit patients with low-risk disease. In the age of novel agents, salvage ASCT can be costeffective and capable of providing durable benefit. But how can we move forward and improve the results of salvage ASCT? From randomized trials performed in patients with newly diagnosed multiple myeloma, we have learned that bortezomib-based and lenalidomidebased induction therapies improve the results prior and after upfront ASCT compared with treatments without any novel agents. 1 In addition, recently published studies demonstrated that thalidomide, lenalidomide, and bortezomib are all capable of enhancing disease control when given after ASCT as part of the initial treatment The results of the current study demonstrated that the outcome of patients can be improved when lenalidomide or bortezomib are used for reinduction therapy, thereby supporting the concept of the early use of novel agents such as lenalidomide and bortezomib in the setting of disease recurrence. 23 For nontransplant candidates, a variety of contemporary regimens are available as options for salvage therapy as listed in the latest version of the National Comprehensive Cancer Network guidelines. 24 In addition, the US Food and Drug Administration recently approved the new proteasome inhibitor carfilzomib for patients with multiple myeloma who develop disease progression during or after therapy with bortezomib and an immunomodulatory derivative such as thalidomide or lenalidomide. 25 So, is there still a place for salvage ASCT when multiple myeloma therapies become more effective in the setting of disease recurrence? Comparative controlled studies in patients with recurrent or refractory multiple myeloma are warranted to help guide clinicians in choosing appropriate salvage therapy. Therefore, we initiated an ongoing phase 3 trial within the German Multiple Myeloma Group study group for patients with recurrent multiple myeloma who are eligible for transplant (European Clinical Trials Database [EudraCT] no ), analyzing the role of ASCT after induction with 3 cycles of lenalidomide and dexamethasone compared with treatment with lenalidomide and dexamethasone until disease progression. Salvage ASCT is capable of achieving sustained disease control in patients with recurrent multiple myeloma. The use of lenalidomide and bortezomib for reinduction has improved the results after salvage ASCT, suggesting that novel agents and salvage ASCT are complementary rather than alternative treatment approaches. Stratification by PFS after upfront ASCT and ISS stage allows for the prediction of survival after salvage ASCT. To circumvent the problem of stem cell harvest in intensively pretreated patients, we recommend the collection and cryopreservation of a sufficient amount of stem cells for both upfront and salvage ASCT early in the course of myeloma treatment. 8 Cancer Month 00, 2013

9 ASCT as Salvage Therapy in MM/Sellner et al FUNDING SUPPORT Supported in part by grants from the Dietmar Hopp Foundation, Heidelberg, Germany; and the Tumorzentrum Heidelberg/ Mannheim, Germany. CONFLICT OF INTEREST DISCLOSURES Drs. Goldschmidt and Neben have received honoraria and research funding and acted as members of an advisory committee for Celgene and Janssen-Cilag. REFERENCES 1. Harousseau JL, Moreau P. Autologous hematopoietic stem-cell transplantation for multiple myeloma. N Engl J Med. 2009;360: Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med. 1996;335: Child JA, Morgan GJ, Davies FE, et al; Medical Research Council Adult Leukaemia Working Party. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003;348: Kumar SK, Rajkumar SV, Dispenzieri A, et al. 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