Early versus delayed autologous transplantation ... - Wiley Online Library

Original Article

Early Versus Delayed Autologous Transplantation After Immunomodulatory Agents-Based Induction Therapy in Patients With Newly Diagnosed Multiple Myeloma Shaji K. Kumar, MD1; Martha Q. Lacy, MD1; Angela Dispenzieri, MD1; Francis K. Buadi, MD1; Suzanne R. Hayman, MD1; David Dingli, MD1; Francesca Gay, MD2; Shirshendu Sinha, MD1; Nelson Leung, MD1; William Hogan, MD1; S. Vincent Rajkumar, MD1; and Morie A. Gertz, MD1

BACKGROUND: Early versus delayed autologous stem cell transplantation (SCT) results in comparable overall survival in patients with multiple myeloma (MM) who receive alkylator-based therapies. It is not clear whether this paradigm holds true in the context of new therapies, such as immunomodulatory drugs (IMiDs). METHODS: The authors studied 290 patients with untreated MM who received IMiD-based initial therapy, including 123 patients who received thalidomide-dexamethasone (TD) and 167 patients who received lenalidomide-dexamethasone (LD) induction before SCT. Patients who underwent a stem cell harvest attempt were considered transplantation-eligible and were included. SCT within 12 months of diagnosis and within 2 months of harvest were considered early SCT (n ¼ 173; 60%). SCT >12 months after diagnosis was considered delayed SCT (n ¼ 112; 40%). RESULTS: In the delayed SCT group, 42 patients had undergone SCT at the time of the current report, and the median estimated time to SCT was 5.3 months and 44.5 months in the early SCT and delayed SCT groups, respectively. The 4-year overall survival rate from diagnosis was 73% in both groups (P ¼ .3) and was comparable in those who received TD (68% vs 64%, respectively) and those who received LD (82% vs 86%, respectively) as initial therapy. The time to progression after SCT was similar between the early and delayed SCT groups (20 months vs 16 months; P value nonsignificant). CONCLUSIONS: The current results indicated that, in transplantation-eligible patients who receive IMiDs as initial therapy followed by early stem cell mobilization, delayed SCT results in similar overall survival compared with early SCT. It is noteworthy that an excellent 4-year survival rate of >80% was observed among transplantation-eligible patients who received initial C 2011 American Cancer therapy with LD regardless of the timing of transplantation. Cancer 2012;118:1585-92. V Society. KEYWORDS: multiple myeloma, stem cell transplantation, lenalidomide, thalidomide, delayed transplantation, survival.

INTRODUCTION The treatment approaches for multiple myeloma (MM) have undergone a dramatic change in the past decade, primarily as a result of the introduction of effective new drugs, such as thalidomide, lenalidomide, and bortezomib.1 Before the introduction of these drugs, the standard approach for patients with newly diagnosed myeloma who were eligible for highdose therapy was initial therapy with dexamethasone alone or combination regimens like vincristine, doxorubicin, and dexamethasone (VAD) for 4 to 6 months followed by high-dose melphalan and peripheral blood stem cell transplantation (SCT).2 This approach was supported by phase 3 trials, which demonstrated a survival improvement for SCT compared with conventional chemotherapy, primarily in patients aged 65 years who are eligible for SCT also benefit from this treatment approach.5 One randomized trial also Corresponding author: Shaji K. Kumar, MD, Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905; Fax: (507) 266-4972; kumar. [email protected] 1 Divisions of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minnesota; 2Division of Hematology, San Giovanni Battista Molinette Hospital, University of Turin, Turin, Italy

S.K.K. and M.A.G. designed the study; S.K.K., M.A.G., and F.G. were involved in data collection; S.K.K. and M.A.G. analyzed the data; and S.K.K., M.Q.L., A.D., F.K.B., S.R.H., D.D., N.L., F.G., S.S., S.V.R., and M.A.G. were involved in writing and critically reviewing the article. DOI: 10.1002/cncr.26422, Received: April 28, 2011; Revised: May 31, 2011; Accepted: June 1, 2011, Published online August 25, 2011 in Wiley Online Library (wileyonlinelibrary.com)

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demonstrated comparable efficacy for SCT applied early in the course of the disease or used as salvage therapy after failure of first line therapy.6 However, early SCT was associated with better quality-of-life parameters, such as time without symptoms and therapy-related toxicity, and an early SCT generally was favored.6 The introduction of novel agents had a profound impact on the initial therapy for myeloma.7-9 Combinations of novel agents with dexamethasone or with other conventional agents result in response rates comparable to those produced in the context of SCT.8,10,11 This degree of efficacy, along with the tolerability of these regimens given long term, has leveled the advantages observed with early SCT and has led to increased use of SCT in a deferred fashion.12 In fact, in many of the recent trials that did not include early SCT as part of the treatment protocol, more than half of the patients opted to continue with induction therapy in favor of a delayed SCT.8 Although it was demonstrated that this approach was comparable to an early SCT in previous trials using alkylator or steroid-based induction therapies, there are no comparable data in the context of induction regimens that contain novel agents. There are several potential concerns about extrapolating the previous data in the context of current regimens. In particular, it is not clear whether patients who relapse after newer therapies will be able to obtain a meaningful response from high-dose melphalan and whether patients will be losing the opportunity to benefit from an effective treatment modality like SCT. Although comparisons between patients who undergo early SCT and those who decided to stay on initial therapy in recent clinical trials have suggested excellent outcomes for both groups,8 it is not clear whether the 2 approaches would provide equivalent benefits to patients with newly diagnosed myeloma. We examined this question in a group of patients with newly diagnosed myeloma who attended our institution and underwent induction with an immunomodulatory drug (IMiD)-dexamethasone (Dex) combination (thalidomide and Dex [Thal-Dex] or lenalidomide and Dex [Len-Dex]).

MATERIALS AND METHODS Four hundred ten consecutive patients with newly diagnosed MM who attended the Mayo Clinic between 2001 and 2008 and received initial therapy with Thal-Dex or Len-Dex formed the initial patient group for this study. Two hundred ninety patients (71%) in whom a stem cell harvest was attempted were considered transplantation

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eligible and were included in the current study. Patients who were started on growth factors for mobilization were included regardless of the outcome of the stem cell mobilization attempt. Patients who underwent SCT within 12 months of diagnosis and within 2 months of stem cell harvest (n ¼ 178; 61%) comprised the early SCT group. The remaining patients (n ¼ 112; 39%), irrespective of whether an SCT eventually was performed, comprised the delayed SCT group. Data pertaining to the patients were captured prospectively into a continuously updated database, and complete follow-up was available for all patients. A small proportion of patients did not undergo their SCT at our institution, and response data pertaining to SCT were not available for several of these patients. All patients provided written informed consent for use of their medical records. Approval from the Mayo Foundation Institutional Review Board was obtained in accordance with federal regulations and the Declaration of Helsinki. The choice of the regimen depended on the period of diagnosis and was dictated by the availability of clinical trials and commercial availability of the drugs. Our standard induction regimen outside of clinical trials was ThalDex until lenalidomide became available commercially, when it was switched to Len-Dex. Thalidomide was given daily at doses from 100 to 400 mg along with dexamethasone 40 mg on days 1 through 4, days 9 through 12, and days 17 through 20 of a 28-day cycle. Lenalidomide was given at standard dose of 25 mg daily on days 1 through 21 along with dexamethasone either as described with thalidomide or at 40 mg weekly according to prevailing practice. Weekly dexamethasone has been the standard practice since publication of the initial results from the Eastern Cooperative Oncology Group E4A03 clinical trial, which demonstrated better survival with weekly dexamethasone.8 Patients routinely received thromboprophylaxis with aspirin; and, in patients who were perceived to be at higher risk for thromboembolic events, full anticoagulation with coumadin or low-molecular-weight heparin was used. Bisphosphonates were administered routinely for prophylaxis against skeletal events in accordance with standard clinical practice. Patients typically proceeded to stem cell collection after 4 to 6 cycles of initial therapy with 1 of these regimens. Stem cells normally were collected using granulocyte–colony-stimulating factor (G-CSF) priming alone with cyclophosphamide and G-CSF limited to those patients who had a poor response to initial therapy and those who had circulating plasma cells at the time of collection according to our clinical practice.

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Timing of Transplantation in Myeloma/Kumar et al

Table 1. Baseline Characteristics From Diagnosis

Variable

Early SCT, n 5 178

Delayed SCT, n 5 112

P

Mean age at diagnosis (range), y Men, % Median hemoglobin (range), g/dL Median platelet count (range), million/mm3 Median calcium (range), mg/dL Median serum creatinine (range), mg/dL LDH, U/L Median bone marrow plasma cells (range), %

58 (29-73) 58 10.9 (7.9-15.9) 140 (11-418) 9.1 (7-11) 0.9 (0.5-3.7) 228 43 (2-90)

61 (32-74) 66 11.4 (8.1-14.6) 154 (21-543) 9.2 (6.8-10.7) 1 (0.6-6.7) 185 40 (1-80)

NS NS NS NS NS NS 1%.14 Chi-square tests and Fisher exact tests were used to compare differences between nominal variables, and the Mann-Whitney U test or the Kruskal-Wallis test was used

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for continuous variables. Kaplan-Meier analysis was used to analyze overall survival (OS) and progression-free survival (PFS). Differences between survival curves were tested for statistical significance using the 2-tailed log-rank test or the Breslow-Gehan test. The time to progression (TTP) was measured from the date of transplantation to the date of disease progression, and patients who died without evidence of relapse were censored at the time of death. PFS was measured from the date of transplantation to the date of either disease progression or death from any cause, and the patients who remained alive and relapse free were censored at the last follow-up. OS was calculated from the date of transplantation or the date of initial diagnosis of myeloma to the date of either death or last follow-up.

RESULTS The median estimated follow-up for the 290 patients who were included in the study was 40 months (95% confidence interval [CI], 36.6-42.6 months) from diagnosis (42 months [95% CI, 40.1-47.5 months] and 34 months [95% CI, 23.8-39.5 months], respectively, for the early SCT group [n ¼ 178] and the delayed SCT group [n ¼ 112]). Two hundred twenty-six patients (78%) were alive at the time of analysis, and the majority of deaths were related to disease progression. The baseline characteristics from diagnosis, which are listed in Table 1, were similar between the 2 groups with the exception of higher lactate dehydrogenase levels in the early SCT group. The median time to stem cell harvest was shorter for the patients who underwent early SCT (4.9 months vs 6.8 months; P < .001) compared with the patients who underwent delayed SCT. Among 112 patients in the delayed SCT group, 42

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Figure 1. (A) Response status at the time of stem cell harvest is illustrated. The x-axis represents the response category. NB indicates not evaluable; PD, progressive disease; MR, minimal response or less; PR, partial response; VGPR, very good partial response; CR, complete response for each group of patients. The y-axis represents the proportion of patients in each response category within each patient group. (B) Overall survival is illustrated from the initiation first therapy for a diagnosis of multiple myeloma in the entire patient group (n ¼ 290). SCT indicates stem cell transplantation. (C) Overall survival is illustrated from the initiation of first therapy for a diagnosis of multiple myeloma among the patients who received initial therapy with thalidomide and dexamethasone (n ¼ 123). (D) Overall survival is illustrated from the initiation of first therapy for a diagnosis of multiple myeloma among patients who received initial therapy with lenalidomide and dexamethasone (n ¼ 167).

patients (37%) underwent SCT for relapsed or refractory disease, and 69 patients in that group received second-line therapy, including SCT. Six patients in the delayed SCT group died without undergoing SCT. The median estimated time to SCT, as expected, was 5.3 months (95% CI, 5.1-5.5 months) in the early SCT group compared with 44.5 months (95% CI, 28.5-54.2 months) in the delayed SCT group. In the entire cohort, initial therapy was Thal-Dex in 123 patients (43%) and Len-Dex in 167 patients (57%). Eighty-six of 290 patients (70%) who received Thal-Dex underwent early SCT compared with 91 patients (55%) who received Len-Dex (P ¼ .01). Response to Primary Therapy and Overall Survival First, we examined the outcome of patients based on treatment approach (early SCT vs delayed SCT). A greater proportion of patients in the delayed SCT group had deeper responses at the time of stem cell harvest; 32% of patients in the delayed SCT group had a very good partial response or better compared with 16% of patients in the early SCT group (P < .01) (Fig. 1A). The median duration of IMiD therapy was 4 months in the early SCT

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group and 9 months in the delayed SCT group. The 4year OS estimate from the time of diagnosis was similar for the early SCT group and the delayed SCT group (72.7% [95% CI, 65%-82%] vs 73.4% [95% CI, 63%88%], respectively; P ¼ .3) (Fig. 1B). We also compared OS from the time of diagnosis between the early SCT group and the delayed SCT group based on the initial regimen. Among the patients who received initial Thal-Dex treatment, the 4-year OS estimate from diagnosis was 67.8% for the early SCT group and 63.6% for the delayed SCT group (P ¼ .5) (Fig. 1C). Similarly, among the patients who received Len-Dex, the estimated 4-year OS rate was 82% for the early SCT group compared with 86% for the delayed SCT group (P ¼ .7) (Fig. 1D). In addition, we examined the TTP after the ‘‘initial line of therapy’’ (induction followed by SCT or continued initial therapy with a plan for delayed SCT). The median TTP after an initial line of therapy was comparable for the 2 groups (25.4 months [95% CI, 23-29 months] for the early SCT group compared with 26.0 months [95% CI, 20-36 months] for the delayed SCT group; P ¼ .9). To date, of 69 patients in the delayed SCT group who received second-line therapy, 42 patients have undergone

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Table 2. Characteristics at Transplantation

Variable

Early SCT (n 5 178)

Delayed SCT (n 5 42)

P

Median age at SCT (range), y Men, % Median serum M protein (range), g/dL Median urine M protein (range), g/24 h Median serum creatinine (range), mg/dL b2-Microglobulin >3.5 mg/dL, % Median LDH (range), U/L Median bone marrow plasma cell (range), % Plasma cell labeling index 1%, %

58 (29-74) 58 0.7 (0-4.4) 0.06 (0-6.1) 0.9 (0.5-3.9) 13 178 (116-853) 7 (0-75) 20

62 (36-76) 60 0.6 (0-7.3) 0.02 (0-1.2) 1 (0.6-4.8) 30 179 (109-1216) 10 (1-67) 41

NS NS NS NS NS 0.03 NS NS .005

Abbreviations: LDH, lactate dehydrogenase; NS, nonsignificant; SCT, stem cell transplantation.

SCT, the remaining patients have pursued non-SCT options, and no differences in OS have been noted between patients who did and did not undergo SCT (data not shown). Because stem cell collection represented the decision-making time point for an early or delayed SCT approach, we also examined OS from that time. The 4-year OS estimate in the early SCT group was 63% compared with 69% in the delayed SCT group (P ¼ .4). The survival estimates were similar between the 2 groups irrespective of the type of IMiD used for induction.

SCT group (P ¼ .4) (Fig. 2A). This was true irrespective of whether they received thalidomide or lenalidomide. From diagnosis, the median TTP after SCT was 25.3 months (95% CI, 22-29 months) in the early SCT group. PFS also was comparable between the groups (19.7 months [95% CI, 6-22 months] for the early SCT group compared with 15.9 months [95% CI, 12-21 months] for the delayed SCT group; P ¼ .09) (Fig. 2B). There was a trend toward better OS after SCT for the early SCT group (65.7% vs 56.3% at 4 years; P ¼ .03; Breslow-Gehan test) (Fig. 2C).

Efficacy of Stem Cell Transplantation Next, we investigated whether the response to high-dose therapy was comparable between patients who underwent early SCT versus delayed SCT. Forty-two patients (37%) in the delayed SCT group were compared with patients in the early SCT group (n ¼ 178). The clinical features at the time of SCT are listed in Table 2. The patients who underwent delayed SCT had higher b2-microglobulin levels and higher rates of proliferation, as expected, because more patients in this group had relapsed disease. The overall response rate to SCT was similar between the 2 groups (92% in the early SCT group compared with 87% in the delayed SCT group; nonsignificant P value). The complete response rate also was similar (35% vs 37% for early SCT vs delayed SCT, respectively; nonsignificant P value). The engraftment kinetics were similar between the 2 groups, with a median time to neutrophil engraftment and platelet engraftment of 13 days (range, 10-34 days) and 15 days (range, 11-528 days), respectively, for the early SCT group and 13 days (range, 10-19 days) and 15 days (range, 11-53 days), respectively, for the delayed SCT group. The median TTP after SCT was 19.7 months (95% CI, 16-22 months) for the early SCT group compared with 18 months (95% CI, 13-21 months) for the delayed

DISCUSSION High-dose therapy and autologous SCT continue to be important components of the treatment approaches for MM in transplantation-eligible patients.1 In fact, myeloma remains the most common indication for autologous SCT in North America according to data reported to the Center for International Blood and Marrow Transplantation Research. The wider adoption of this modality has resulted from randomized trials that demonstrated a survival benefit for this approach compared with conventional nontransplantation approaches. However, results from the initial trials also suggest that the improved outcome with SCT may be a reflection of the depth of response, and an OS improvement was not observed consistently in all trials.15-17 The results from the phase 3 US Intergroup Trial S9321 suggested that the survival advantage may not persist once the complete response rates to conventional therapy improve.16 The introduction of newer, more effective therapies like IMiDs and the proteasome inhibitor bortezomib has led to high response rates and deeper responses and has raised questions regarding the continued role of SCT in this disease. Because of the high response rates observed at the end of induction therapy and the low toxicity profile of current regimens, patients increasingly are opting to delay SCT and continue

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Figure 2. (A) The time to progression after stem cell transplantation (SCT) is illustrated for patients who underwent early SCT (n ¼ 178) or delayed SCT (n ¼ 42). (B) Progression-free survival after SCT is illustrated for patients who underwent early SCT (n ¼ 178) or delayed SCT (n ¼ 42). (C) Overall survival after SCT is illustrated for patients who underwent early SCT (n ¼ 178) or delayed SCT (n ¼ 42).

with initial therapy.8,12 This raises important questions regarding the efficacy of SCT in the context of patients who have disease that is refractory to novel therapies and whether such a delay may compromise the eventual benefit that patients may obtain with this procedure. In the current study, we were able to demonstrate that the paradigm of comparable survival with early or delayed SCT holds true in the context of newer therapies as it did for the alkylator-based regimens of the past. The

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results are true irrespective of the specific IMiD used, whether thalidomide or lenalidomide, further confirming that the equivalence of SCT used in an early or deferred fashion is independent of therapy. It may be argued that more patients received thalidomide in the early transplantation group, but the comparisons hold true irrespective of the initial drug used. Differences in the proportion of patients on the 2 drugs between the groups likely reflect the better tolerability of lenalidomide and the increasing comfort on the part of physicians to defer transplantation with the availability of more long-term data for lenalidomide. The results serve to further underscore that SCT should be considered as a therapeutic regimen, like any other drug regimen, and not necessarily as a platform on which to base other therapies. This concept is supported further by the comparable TTP after ‘‘first-line therapy,’’ whether it was induction therapy followed by early SCT or continued primary therapy with the intent to undergo delayed SCT. This is not surprising given the comparable response rates and depth of response observed with early SCT versus continued primary therapy from phase 2 trials and subgroup analyses of phase 3 trials. Thus, it is reasonable to assume that short induction therapy followed by SCT and continued induction therapy until patients develop disease progression represent 2 comparable ‘‘regimens’’ in terms of the duration of disease control and 2 noncross-resistant approaches that can be used in any order. We included only patients who received IMiDbased induction therapy in this study, because very few of our patients were initiated on bortezomib-based regimens, given the predominantly referral nature of our patient population and the preference for oral regimens. It is likely that the results will hold true for patients who also receive other, effective agents. An important finding from the current study is the 4 year OS rate of >80% in a group of transplantation-eligible patients who received Len-Dex as primary therapy with the intent of either early or deferred SCT. This is comparable to the results reported with multidrug combination therapies, highlighting the need to study sequential approaches using currently available drugs versus combination approaches in prospective studies and simultaneously examining the impact on quality of life. Another important finding from the current study was the comparable TTP after early or delayed SCT. This is in stark contrast to the results from previous randomized trials that examined early versus delayed SCT. In the MAG90 trial, delayed SCT was associated with a shorter TTP after SCT, although the OS rate was comparable between the 2 approaches.6 The type of primary therapy

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received by patients who chose delayed SCT likely explains this. Unlike earlier trials in which patients were alkylator refractory or previously responsive to alkylating agents, all patients who underwent delayed SCT in this study were alkylator naive at the time of SCT. In this regard, they were similar to their counterparts who elected to undergo early SCT. However, there was a trend toward shorter OS survival after SCT in the delayed SCT group. This is explained by the fact that these patients had ‘‘used up’’ 1 of the available treatment options, as they went on to transplantation after they had a relapse following continued therapy with an IMiD. The aspect of an early transplantation approach, which traditionally has tilted the decision in favor of early transplantation, has been the reduced time without the symptoms and side effects of therapy observed in phase 3 trials.6 However, this paradigm has changed with the newer agents, which are tolerated much better and often can be continued for prolonged duration with minimal toxicity and impact on quality of life. Hence, it is not surprising that there is increased acceptance of the delayed SCT approach. The current study, which was retrospective in nature, did not allow for a comparison of qualityof-life parameters between the 2 approaches. This will have to be explored in the context of prospective trials comparing early SCT with delayed SCT. The decision to proceed to an early SCT or to defer transplantation until a patient develops a relapse can be based on several factors, including response to induction therapy, toxicity from treatment, physician bias, and patient perception, among others. In the current study, the proportion of patients with deep responses was greater among those who decided to defer SCT, a finding that undoubtedly would have influenced the decision. However, a recent study of patients who underwent SCT revealed inferior survival for patients who obtained less than a partial response to initial therapy with an IMiD, unlike what was reported in the pre-IMiD era.18 This does not necessarily contradict the current findings, because >33% of patients who had less than a partial response opted for delayed SCT and alternative therapies. The retrospective nature of the current study precludes an accurate determination of the reasons for deciding on early SCT versus delayed SCT. Also, the current study addressed the use of SCT primarily as second-line therapy, which was the common practice in this patient group, and the results cannot necessarily be extrapolated to patients who underwent SCT after failing multiple lines of therapy with different, newer drugs.

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However, it is important to underscore that nearly all patients underwent early stem cell collection, even when delayed SCT was planned. However, in the group that delayed SCT, the median time to stem cell collection was 6.8 months, representing 6 to 7 cycles of therapy. This is very important, because several studies have established that there is an increased risk of collection failure for patients who receive lenalidomide as initial therapy; whereas the impact of thalidomide or bortezomib appears to be less profound.19-22 The duration of therapy appears to be a strong predictor, along with age, of the risk of stem cell collection failure.19 However, if a deferred stem cell collection approach had been used at the time of stem cell transplantation, then the results may have been different, because more patients would have failed stem cell collection and, thus, would have been unable to proceed to SCT. Finally, the 4-year survival rate of >80% among patients who received Len-Dex as initial therapy highlights the impact of newer therapies on patient outcome in myeloma. This is comparable to the results observed in subanalyses from the E4A03 clinical trial, which focused on patients undergoing SCT after Len-Dex induction therapy.23 Moreover, in this group of transplantation-eligible patients receiving Len-Dex as initial therapy, the timing of transplantation did not appear to alter the OS outcome. In conclusion, this study conveys 3 important messages. First, it confirms the role of SCT as an effective treatment strategy for patients with myeloma with comparable survival outcomes when applied early in the course of disease or in a deferred manner after failure of continued initial therapy. Second, it highlights the retained efficacy of high-dose melphalan in alkylator-naive patients, demonstrating noncross-resistant mechanisms for disease control for these 2 approaches. Third, it demonstrates an excellent long-term outcome for patients who receive initial LenDex therapy, who have an OS rate >80% at 4 years. Thus, patients have the option of delaying SCT and continuing with initial therapy if that is their preference. However, it is important to collect stem cells early on, given the reports of difficult stem cell collection in patients who receive prolonged treatment with lenalidomide. Whether such an approach will result in comparable quality-of-life metrics needs to be studied prospectively.

FUNDING SOURCES This study was supported in part by the Hematological Malignancies Program (Mayo Clinic Cancer Center) and by grant CA90628 from the National Cancer Institute (to S.K.K.).

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CONFLICT OF INTEREST DISCLOSURES S.K.K. has received research support to the Mayo Clinic for the conduct of clinical trials in the role of principal investigator from Celgene, Millennium Pharmaceuticals, Genzyme, Novartis, Bayer, and Cephalon and has participated on the advisory boards of Merck and Celgene. M.A.G. has received honoraria from Easai Pharmaceuticals, Millennium Pharmaceuticals, Amgen, and Celgene. A.D. and M.Q.L. have received research support to the Mayo Clinic for the conduct of clinical trials in the role of principal investigator from Celgene. F.G. has received honoraria from Celgene.

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March 15, 2012