VOLUME 35 • NUMBER 29 • OCTOBER 10, 2017 JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T Lenalidomide Maintenance After Autologous Stem-Cell Transplantation in Newly Diagnosed Multiple Myeloma: A Meta-Analysis Philip L. McCarthy, Sarah A. Holstein, Maria Teresa Petrucci, Paul G. Richardson, Cyrille Hulin, Patrizia Tosi, Sara Bringhen, Pellegrino Musto, Kenneth C. Anderson, Denis Caillot, Francesca Gay, Philippe Moreau, Gerald Marit, Sin-Ho Jung, Zhinuan Yu, Benjamin Winograd, Robert D. Knight, Antonio Palumbo, and Michel Attal Author affiliations and support information (if applicable) appear at the end of this article. Published at jco.org on July 25, 2017. Processed as a Rapid Communication manuscript. Clinical trial information: NCT00551928, NCT00551928, NCT00430365. Corresponding author: Philip L. McCarthy, MD, Blood and Marrow Transplant Program, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263; e-mail: philip.mccarthy@ roswellpark.org. © 2017 by American Society of Clinical Oncology 0732-183X/17/3529w-3279w/$20.00 A B S T R A C T Purpose Lenalidomide maintenance therapy after autologous stem-cell transplantation (ASCT) demonstrated prolonged progression-free survival (PFS) versus placebo or observation in several randomized controlled trials (RCTs) of patients with newly diagnosed multiple myeloma (NDMM). All studies had PFS as the primary end point, and none were powered for overall survival (OS) as a primary end point. Thus, a meta-analysis was conducted to better understand the impact of lenalidomide maintenance in this setting. Patients and Methods The meta-analysis was conducted using primary-source patient-level data and documentation from three RCTs (Cancer and Leukemia Group B 100104, Gruppo Italiano Malattie Ematologiche dell’Adulto RV-MM-PI-209, and Intergroupe Francophone du Myélome 2005-02) that met the following prespecified inclusion criteria: an RCT in patients with NDMM receiving ASCT followed by lenalidomide maintenance versus placebo or observation with patient-level data available and achieved database lock for primary efficacy analysis. Results Overall, 1,208 patients were included in the meta-analysis (605 patients in the lenalidomide maintenance group and 603 in the placebo or observation group). The median PFS was 52.8 months for the lenalidomide group and 23.5 months for the placebo or observation group (hazard ratio, 0.48; 95% CI, 0.41 to 0.55). At a median follow-up time of 79.5 months for all surviving patients, the median OS had not been reached for the lenalidomide maintenance group, whereas it was 86.0 months for the placebo or observation group (hazard ratio, 0.75; 95% CI, 0.63 to 0.90; P = .001). The cumulative incidence rate of a second primary malignancy before disease progression was higher with lenalidomide maintenance versus placebo or observation, whereas the cumulative incidence rates of progression, death, or death as a result of myeloma were all higher with placebo or observation versus lenalidomide maintenance. Conclusion This meta-analysis demonstrates a significant OS benefit and confirms the PFS benefit with lenalidomide maintenance after ASCT in patients with NDMM when compared with placebo or observation. J Clin Oncol 35:3279-3289. © 2017 by American Society of Clinical Oncology INTRODUCTION ASSOCIATED CONTENT See accompanying Editorial on page 3269 Data Supplements DOI: https://doi.org/10.1200/JCO. 2017.72.6679 DOI: https://doi.org/10.1200/JCO.2017. 72.6679 After induction therapy, patients with newly diagnosed multiple myeloma (NDMM) may be treated with high-dose melphalan (HDM) and autologous stem-cell transplantation (ASCT).1-4 ASCT is not curative, and most patients will experience progressive disease (PD),5-8 even patients who attain a complete response.9-11 Strategies to delay PD include achieving a deep response after ASCT12-15 and sustaining response with maintenance therapy to provide long-term disease control.9,16,17 Effective maintenance therapy should be convenient for the patient, extend remission, and have a tolerable safety profile.3,18 The immunomodulatory drug lenalidomide has been shown to © 2017 by American Society of Clinical Oncology Downloaded from ascopubs.org by 52.73.204.196 on May 16, 2022 from 052.073.204.196 Copyright © 2022 American Society of Clinical Oncology. All rights reserved. 3279 McCarthy et al improve progression-free survival (PFS) and overall survival (OS) in patients with NDMM and relapsed or refractory multiple myeloma (MM).2,19-24 Lenalidomide modulates the immune response, inhibits MM growth, and is suitable for maintenance therapy after ASCT.1,3,18,25 In three studies,2,19,20 lenalidomide maintenance after ASCT reduced the risk of progression or death by 50% to 58% versus placebo or observation, and one of these studies showed a significant OS improvement.19 The primary end point of these studies was PFS, and the studies were not powered for a primary OS end point. In addition, second primary malignancies (SPMs) were reported in patients receiving lenalidomide maintenance after HDM and ASCT.19,20 A meta-analysis was conducted at the request of the US Food and Drug Administration to evaluate the effect of postASCT lenalidomide maintenance on outcomes, including OS, in patients with NDMM. PATIENTS AND METHODS Study Identification and Selection We examined all randomized controlled trials (RCTs) evaluating maintenance treatment with lenalidomide after HDM and ASCT. Inclusion criteria included RCT in patients with NDMM receiving post-ASCT lenalidomide before progression; maintenance comparing a lenalidomide arm to a placebo or observation arm; achieved database lock for the primary efficacy analysis; and primary-source patient-level data or available documentation. A search of the PubMed database using the keywords “lenalidomide,” “maintenance,” and “myeloma” found no other studies. We identified 17 studies (Data Supplement) and the following three studies met the prespecified inclusion criteria: Cancer and Leukemia Group B (CALGB) 100104 (A Phase III Randomized, Double-Blind Study of Maintenance Therapy With Lenalidomide or Placebo Following Autologous Stem Cell Transplantation for Multiple Myeloma)19; Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) RV-MM-PI-209 (A Phase III, Multicenter, Randomized, Controlled Study to Determine the Efficacy and Safety of Lenalidomide, Melphalan, and Prednisone Versus Melphalan (200 mg/m2) Followed by Stem Cell Transplant in Patients with Newly Diagnosed Multiple Myeloma)2; and Intergroupe Francophone du Myélome (IFM) 2005-02 (Relevance of Maintenance Therapy Using Lenalidomide After Autologous Stem Cell Transplantation Patients Under the Age of 65)20. The Myeloma XI trial (Use of Thalidomide, Lenalidomide, Carfilzomib, Bortezomib and Vorinostat in the Initial Treatment of Newly Diagnosed Multiple Myeloma Patients)26 had not completed accrual at the data cutoff date, and the other 13 studies did not compare lenalidomide maintenance with placebo or observation. Additional study details are provided in the Data Supplement. The human investigations for the CALGB study were performed after approval by a local or central human investigations committee and in accordance with an assurance filed with and approved by the Department of Health and Human Services. The IFM and GIMEMA studies were performed after approval by a local or central human investigations committee in accordance with the European Medicines Agency. All data were anonymized to protect the identities of patients involved in the research. All investigators obtained informed consent from each participant or each participant’s guardian. Outcome Measures The primary end point for the meta-analysis was OS. Other analyses included PFS, PFS after next therapy (PFS2), duration of maintenance treatment, time to second antimyeloma treatment, and safety. Individual analyses of OS, PFS, and PFS2 for each study were performed. All analyses used patient-level data from each study. Additional end point analytic details are provided in the Data Supplement. 3280 Statistical Analysis A 20-month improvement in median OS from 70 months for the placebo or observation control group to 90 months in the lenalidomide maintenance group, representing a hazard ratio (HR) of 0.78, was considered clinically relevant. March 1, 2015 was the cutoff date for the metaanalysis on the basis of number of events required. All patients were evaluated on an intent-to-treat (ITT) basis after ASCT. Additional methods, including sensitivity, heterogeneity, and exploratory analytic details, are presented in the Data Supplement. RESULTS Patient Demographics A total of 1,208 patients composed the ITT population; 605 patients were in the lenalidomide maintenance group, and 603 patients were in the placebo or observation group (Data Supplement). The ITT population included all patients who were randomly assigned to lenalidomide versus placebo or observation and who received HDM or ASCT, regardless of whether they received maintenance therapy. As of the March 1, 2015, data cutoff, the median follow-up time for all surviving patients was 79.5 months (range, 0.0 to 114.3 months). Patient demographics and disease-related characteristics were generally balanced based on available data, except for International Staging System (ISS) disease stage, cytogenetics, and renal function, which favored the placebo or observation group (P , .1; Table 1). The median age was approximately 58 years. Additional details on patient demographics and disease evaluation after ASCT and before maintenance therapy are provided in the Data Supplement. Maintenance treatment duration was affected by study changes within the CALGB study (allowing crossover from placebo to lenalidomide at unblinding before PD) and the IFM study (stopping maintenance in 119 patients without PD). Maintenance therapy durations are listed in Table 2. The percentages of patients receiving lenalidomide for $ 4 years were 24.1% in CALGB, 3.6% in IFM (which includes 2 cycles of lenalidomide consolidation), and 42.9% in the GIMEMA study. The mean treatment duration was 28 months with lenalidomide maintenance and 22 months with placebo or observation (Table 2). PFS In this meta-analysis, the significant PFS improvement observed with lenalidomide maintenance versus placebo or observation was confirmed. The median PFS time was 52.8 months for the lenalidomide group and 23.5 months for the placebo or observation group. The risk of progression or death was reduced by 52% with lenalidomide maintenance versus placebo or observation (HR, 0.48; 95% CI, 0.41 to 0.55; Fig 1A). Results were consistent when alternative censoring rules were applied (Data Supplement). The PFS improvement with lenalidomide maintenance versus placebo or observation was confirmed in each study (Fig 1B) and was seen in all subgroups that had data available from all three studies (Fig 1C). Subgroup analysis of data not available from all three studies is presented in the Data Supplement. Lenalidomide maintenance improved PFS in all subgroups, including patients with high-risk cytogenetics; however, the majority of patients did not have available cytogenetic data. © 2017 by American Society of Clinical Oncology Downloaded from ascopubs.org by 52.73.204.196 on May 16, 2022 from 052.073.204.196 Copyright © 2022 American Society of Clinical Oncology. All rights reserved. JOURNAL OF CLINICAL ONCOLOGY Lenalidomide Maintenance After ASCT in Multiple Myeloma Table 1. Demographics and Disease-Related Characteristics at Diagnosis (intent-to-treat population) No. of Patients (%) CALGB Characteristic* Len Maintenance (n = 231) IFM Placebo (n = 229) Len Maintenance (n = 307) GIMEMA Placebo (n = 307) Len Maintenance (n = 67) Observation (n = 67) Pooled Len Maintenance (n = 605) Placebo or Observation (n = 603) Age, years† Median (range) 58.0 (29.0-71.0) 58.0 (39.0-71.0) 57.5 (22.7-68.3) 58.1 (32.3-67.0) 57.9 (35.5-65.1) 56.2 (40.1-66.0) 58.0 (22.7-71.0) 57.9 (32.3-71.0) # 59 131 (56.7) 133 (58.1) 198 (64.5) 194 (63.2) 43 (64.2) 48 (71.6) 372 (61.5) 375 (62.2) $ 60 100 (43.3) 96 (41.9) 109 (35.5) 113 (36.8) 24 (35.8) 19 (28.4) 233 (38.5) 228 (37.8) Male 121 (52.4) 129 (56.3) 169 (55.0) 181 (59.0) 32 (47.8) 39 (58.2) 322 (53.2) 349 (57.9) Race White 175 (75.8) 171 (74.7) — — 65 (97.0) 67 (100) 240 (39.7) 238 (39.5) Nonwhite 42 (18.2) 47 (20.5) — — 2 (3.0) 0 44 (7.3) 47 (7.8) Missing data 14 (16.1) 11 (4.8) 307 (100) 307 (100) 0 0 321 (53.1) 318 (52.7) ISS stage‡§k I 62 (26.8) 85 (37.1) 128 (41.7) 143 (46.6) 35 (52.2) 41 (61.2) 225 (37.2) 269 (44.6) II 58 (25.1) 46 (20.1) 104 (33.9) 107 (34.9) 24 (35.8) 17 (25.4) 186 (30.7) 170 (28.2) III 39 (16.9) 35 (15.3) 66 (21.5) 46 (15.0) 8 (11.9) 9 (13.4) 113 (18.7) 90 (14.9) Missing data 72 (31.2) 63 (27.5) 9 (2.9) 11 (3.6) 0 0 81 (13.4) 74 (12.3) Extramedullary disease Yes 54 (23.4) 69 (30.1) 30 (9.8) 28 (9.1) 10 (14.9) 10 (14.9) 94 (15.5) 107 (17.7) No 160 (69.3) 149 (65.1) 277 (90.2) 278 (90.6) 57 (85.1) 57 (85.1) 494 (81.7) 484 (80.3) Missing data 17 (7.4) 11 (4.8) 0 1 (0.3) 0 0 17 (2.8) 12 (2.0) Adverse-risk cytogenetics, t(4;14) or del17pk¶ Yes — — 41 (13.4) 24 (7.8) 15 (22.4) 12 (17.9) 56 (9.3) 36 (6.0) No — — 202 (65.8) 216 (70.4) 30 (44.8) 27 (40.3) 232 (38.3) 243 (40.3) Missing data — — 64 (20.8) 67 (21.8) 22 (32.8) 28 (41.8) 317 (52.4) 324 (53.7) Lactate dehydrogenase Normal — — 208 (67.8) 220 (71.7) 62 (92.5) 63 (94.0) 270 (44.6) 283 (46.9) . ULN — — 40 (13.0) 41 (13.4) 5 (7.5) 4 (6.0) 45 (7.4) 45 (7.5) Missing data — — 59 (19.2) 46 (15.0) 0 0 290 (47.9) 275 (45.6) Creatinine clearance, mL/mink¶ , 50 11 (4.8) 9 (3.9) 45 (14.7) 25 (8.1) 4 (6.0) 3 (4.5) 60 (9.9) 37 (6.1) $ 50 60 (26.0) 64 (27.9) 204 (66.4) 232 (75.6) 63 (94.0) 64 (95.5) 327 (54.0) 360 (59.7) Missing data 160 (69.3) 156 (68.1) 58 (18.9) 50 (16.3) 0 0 218 (36.0) 206 (34.2) NOTE. Dash indicates not reported. Abbreviations: CALGB, Cancer and Leukemia Group B; GIMEMA, Gruppo Italiano Malattie Ematologiche dell’Adulto; IFM, Intergroupe Francophone du Myélome; ISS, International Staging System; Len, lenalidomide; ULN, upper limit of normal. *Race was not collected in the IFM 2005-02 study, and lactate dehydrogenase and cytogenetics data were not available for the CALGB 100104 study. †For the CALGB 100104 and IFM 2005-02 studies, age at random assignment was available or used. For the GIMEMA study, only age at diagnosis was available. ‡P , .1 for the comparison of ISS stages I, II, and III individually. The ISS stage was based on b2-microglobulin and albumin at diagnosis for the GIMEMA RV-MM-PI-209 and IFM 2005-02 studies and at registration for the CALGB 100104 study. §P , .1 for the comparison between the lenalidomide maintenance arm and placebo arm in the CALGB study using the t test for continuous variables and Fisher’s exact test for categorical variables. kP , .1 for the comparison between the lenalidomide maintenance group and placebo or observation group in the pooled analysis using the t test for continuous variables and Fisher’s exact test for categorical variables. ¶P , .1 for the comparison between the lenalidomide maintenance arm and placebo arm in the IFM 2005-02 study using the t test for continuous variables and Fisher’s exact test for categorical variables. OS As of the March 1, 2015, data cutoff, 490 deaths occurred in both cohorts. Median OS was not reached in the lenalidomide maintenance group and was 86.0 months in the placebo or observation group (HR, 0.75; 95% CI, 0.63 to 0.90; P = .001), representing a 25% reduction in the risk of death with lenalidomide maintenance versus placebo or observation (Fig 2A). Fisher’s combination test confirmed the significant OS benefit with lenalidomide maintenance versus placebo or observation (P = .001). The 7-year survival rate was 62% with lenalidomide maintenance and 50% with placebo or observation. At the median follow-up time jco.org of 79.5 months, 64% and 54% of patients were alive in the lenalidomide maintenance and placebo or observation groups, respectively. The proportional hazards (PH) assumption was tested using the time-dependent covariate in the PH Cox model; the proportionality was not significant (P = .21). The graphical check of the PH assumption using the 2log (2log) plot of the estimated survival function for each treatment group revealed the same results. The OS subgroup analyses are shown in Figure 2B. Except for patients with ISS disease stage III, the HRs for the subgroup analyses favor lenalidomide maintenance. Patients with better responses ($ very good partial response) after HDM or ASCT seemed to have © 2017 by American Society of Clinical Oncology Downloaded from ascopubs.org by 52.73.204.196 on May 16, 2022 from 052.073.204.196 Copyright © 2022 American Society of Clinical Oncology. All rights reserved. 3281 McCarthy et al Table 2. Duration of Maintenance Therapy (safety population) CALGB IFM* Len Maintenance (n = 306) Placebo (n = 221) Treatment Duration Len Maintenance (n = 224) Placebo Up to Crossover (n = 221) Mean, months (range)§ Duration category, No. (%) $ 1 year $ 2 years $ 3 years $ 4 years 30 (0-108) 13 (0-51) 25 (0-61) 95 32 6 1 46 33 24 18 150 116 82 54 (67.0) (51.8) (36.6) (24.1) (43.0) (14.5) (2.7) (0.5) Len After Crossover (n = 76)† All Patients (n = 306) Cohort Treatment Stopped Jan 2011 (n = 119)‡ 25 (0-55) 39 (27-55) (60.5) (43.4) (31.6) (23.7) 217 170 88 11 (70.9) (55.6) (28.8) (3.6) 119 119 74 11 (100) (100) (62.2) (9.2) GIMEMA Placebo (n = 302) Len Maintenance (n = 56) 20 (0-49) 211 121 32 2 (69.9) (40.1) (10.6) (0.7) Pooled Observation (n = 67) Len Maintenance (n = 586) Placebo or Observation (n = 590) 35 (2-71) 29 (0-75) 28 (0-108) 22 (0-86) 44 33 29 24 51 36 23 17 (78.6) (58.9) (51.8) (42.9) (76.1) (53.7) (34.3) (25.4) 411 319 199 89 (70.1) (54.4) (34.0) (15.2) 391 230 95 44 (66.3) (39.0) (16.1) (7.5) NOTE. Safety population includes patients who received at least one dose of study drug. Abbreviations: CALGB, Cancer and Leukemia Group B; GIMEMA, Gruppo Italiano Malattie Ematologiche dell’Adulto; IFM, Intergroupe Francophone du Myélome; Len, lenalidomide. *In the IFM study, data from two cycles of lenalidomide consolidation are included. †In the CALGB study, after study unblinding on December 17, 2009, patients randomly assigned to the placebo arm were allowed to cross over to lenalidomide before progressive disease. ‡In the IFM study, treatment was stopped in the lenalidomide arm in January 2011 for 119 patients (minimum treatment duration of 27 months) after observing an imbalance of second primary malignancies in the lenalidomide arm. §Only mean values are reported due to treatment time truncation from the IFM 2005-02 study and median times cannot be given for the IFM 2005-02 study. more favorable outcomes with lenalidomide maintenance. The most favorable OS benefit with lenalidomide maintenance was observed in patients who received a lenalidomide-based induction treatment (Fig 2C). Subgroup analysis of data not available for all three studies is presented in the Data Supplement. An OS improvement with lenalidomide maintenance was not seen in the following diagnostic subgroups: elevated lactate dehydrogenase, low creatinine clearance, and adverse-risk cytogenetics; however, not all patients had available information. Heterogeneity and Exploratory Analyses The Pignon heterogeneity test indicated a significant difference in quantitative treatment effect across studies (P = .047). No qualitative heterogeneity in OS was found using the Gail-Simon test (P = .75), indicating no directional difference in treatment effect. Thus, the HRs of the individual studies all favored lenalidomide maintenance treatment (Fig 2D). The heterogeneity observed is driven by the difference in magnitude of the treatment effect among the studies. A simplified multivariate analysis with treatment, study, and treatment by study interaction in the model revealed similar results; the heterogeneity in OS was mainly a result of differences between the CALGB and IFM studies (P = .015 for treatment by study [CALGB v IFM] interaction). There was no significant heterogeneity in OS between CALGB and GIMEMA (P = .525 for treatment by study [CALGB v GIMEMA] interaction). There were differences between the three studies regarding pre- and post-ASCT patient characteristics and treatment. These differences include prestudy patient characteristics, induction regimens, consolidation therapies (Data Supplement), and secondline therapies (Data Supplement), as well as changes in study conduct such as post-ASCT lenalidomide consolidation in the IFM trial, crossover from placebo to lenalidomide after unblinding in the CALGB trial, and stopping of lenalidomide maintenance therapy in the IFM trial (Data Supplement). With extended followup (February 1, 2016), lenalidomide maintenance reduced the risk 3282 of death by 23% compared with placebo or observation (HR, 0.77; 95% CI, 0.65 to 0.91; P = .002). The median OS time was 111.0 months with lenalidomide maintenance compared with 86.9 months with placebo or observation. The median duration of follow-up among all surviving patients was 88.8 months (range, 0 to 119.8 months). Heterogeneity in OS across studies was not detected by the Pignon test with the longer follow-up (P = .10). PFS2 Median PFS2 was 73.3 months with lenalidomide maintenance compared with 56.7 months with placebo or observation (HR, 0.72; 95% CI, 0.62 to 0.84; Data Supplement). Lenalidomide maintenance reduced the risk of a PFS2 event (progression on second-line treatment or death) by 28% compared with placebo or observation. The PFS2 HRs in all studies favored lenalidomide maintenance versus placebo or observation (Data Supplement). Second-Line Antimyeloma Treatment Time to second-line antimyeloma treatment was prolonged with lenalidomide maintenance versus placebo or observation (HR, 0.57; 95% CI, 0.49 to 0.66; Data Supplement). Fewer patients in the lenalidomide maintenance group (52.6%) started secondline antimyeloma therapy compared with patients in the placebo or observation group (70.8%). The most common second-line antimyeloma treatment was lenalidomide based (27.9%) in the placebo or observation group and bortezomib based (19.5%) in the lenalidomide maintenance group. Safety Treatment-emergent adverse events (TEAEs) were analyzed for patients in the CALGB and IFM trials. Data were not available from GIMEMA. Rates of treatment discontinuation as a result of TEAEs were 29.1% in the lenalidomide maintenance group and 12.2% in the placebo or observation group (Table 3). The most © 2017 by American Society of Clinical Oncology Downloaded from ascopubs.org by 52.73.204.196 on May 16, 2022 from 052.073.204.196 Copyright © 2022 American Society of Clinical Oncology. All rights reserved. JOURNAL OF CLINICAL ONCOLOGY Lenalidomide Maintenance After ASCT in Multiple Myeloma A B No. of Events/ No. of Median PFS (95% CI) Patients 52.8 months Len 316/605 (45.1 to 62.6) maintenance 1.0 HR (95% CI) HR (95% CI) CALGB (n = 460) 0.38 (0.29 to 0.50) IFM (n = 614) 0.53 (0.43 to 0.64) GIMEMA (n = 134) 0.50 (0.31 to 0.80) Pooled (N = 1,208) 0.48 (0.41 to 0.55) 0.48 (0.41 to 0.55) Placebo/ observation PFS (probability) 0.8 411/603 23.5 months (21.0 to 26.2) 0.6 0.4 0.25 0.5 1 2 HR* 0.2 Favors Len Maintenance 0 Favors Placebo/ Observation 10 20 30 40 50 60 70 80 90 100 110 120 Time (months) No. at risk: Len maintenance Placebo/ observation 605 499 428 353 293 244 191 131 83 28 5 603 419 275 179 125 90 9 0 71 52 30 0 C Len Maintenance (No. of patients) Placebo/ Observation (No. of patients) HR (95% CI) ≤ 59 372 375 0.45 (0.37 to 0.55) ≥ 60 233 228 0.51 (0.40 to 0.66) Male 322 349 0.40 (0.32 to 0.48) Female 283 254 0.58 (0.46 to 0.73) I/II 411 439 0.46 (0.38 to 0.55) III 113 90 0.57 (0.40 to 0.81) Age (years)† Sex ISS stage‡ CR 65 80 0.56 (0.34 to 0.93) Response after ASCT (prior to maintenance) CR/VGPR 314 334 0.48 (0.39 to 0.60) PR/SD§ 227 215 0.47 (0.37 to 0.60) Len 147 145 0.44 (0.31 to 0.62) Non-Len 458 458 0.49 (0.41 to 0.58) Prior induction therapy 0.25 0.5 1 2 4 HR Favors Len Maintenance Favors Placebo/ Observation Fig 1. Progression-free survival (PFS) analysis (intent-to-treat population). For analyses of PFS, patients who started another antimyeloma therapy before documented disease progression or patients with missing assessments are censored. (A) Kaplan-Meier estimates of PFS. (B) Hazard ratios (HRs) for PFS by individual study. (C) HRs for PFS by subgroup. (*) The size of each blue box corresponds to the size of the individual study. The CI is a function of the overall sample size. (†) Age at random assignment was available and used for the Cancer and Leukemia Group B (CALGB) 100104 study19 and the Intergroupe Francophone du Myélome (IFM) 2005-02 study20. Only age at diagnosis was available for the Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) RV-MM-PI-209 study2. (‡) The International Staging System (ISS) stage was based on b2-microglobulin and albumin at diagnosis for the GIMEMA and IFM studies and at registration for the CALGB study. (§) Upon central review, four patients did not meet the criteria for stable disease (SD). ASCT, autologous stem-cell transplantation; CR, complete response; Len, lenalidomide; PR, partial response; VGPR, very good partial response. common TEAEs leading to treatment discontinuation in the lenalidomide maintenance and placebo or observation groups were blood and lymphatic system disorders (4.3% v 2.1%, respectively) jco.org and general disorders and administration site conditions (4.7% v 1.5%, respectively). Consistent with previous CALGB and IFM reports, this analysis showed a higher frequency of SPMs with © 2017 by American Society of Clinical Oncology Downloaded from ascopubs.org by 52.73.204.196 on May 16, 2022 from 052.073.204.196 Copyright © 2022 American Society of Clinical Oncology. All rights reserved. 3283 McCarthy et al Placebo/ Len Maintenance Observation (No. of (No. of patients) patients)* B A 1.0 ≤ 59 Age (years)* ≥ 60 Male Sex Female I/II ISS stage† III CR Response CR/VGPR after ASCT PR/SD‡ (prior to maintenance) 0.25 OS (probability) 0.8 0.6 0.4 0.2 0 No. of Events/ No. of Patients 372 233 322 283 411 113 65 314 227 0.5 1 2 375 228 349 254 439 90 80 334 215 HR (95% CI) 0.68 (0.54 to 0.86) 0.85 (0.64 to 1.12) 0.66 (0.52 to 0.83) 0.92 (0.70 to 1.21) 0.66 (0.52 to 0.82) 1.06 (0.73 to 1.54) 0.63 (0.34 to 1.15) 0.70 (0.54 to 0.90) 0.88 (0.66 to 1.17) 4 HR Median OS HR (95% CI) (95% CI) Len NR maintenance 215/605 (NR to NR) 0.75 (0.63 to 0.90) 86.0 months Placebo/ 275/603 (79.8 to 96.0) observation Favors Len Favors Placebo/ Maintenance Observation 10 20 30 40 50 60 70 80 90 100 110 120 Time (months) No. at risk: Len 605 577 555 508 473 431 385 282 200 95 maintenance Placebo/ observation 603 569 542 505 459 425 351 270 174 71 C 20 1 10 0 0 Len Maintenance Placebo/ (No. of Observation patients)§ (No. of patients)§ HR (95% CI) Len based 147 145 0.50 (0.32 to 0.77) No Len 458 458 0.82 (0.67 to 1.00) Thalidomide based or TD 112 114 0.73 (0.49 to 1.11) No thalidomide or TD 493 489 0.76 (0.62 to 0.93) Bortezomib based or VD 239 225 0.76 (0.57 to 1.02) No bortezomib or VD 366 378 0.74 (0.59 to 0.93) Anthracycline based or VAD 185 420 No anthracycline or VAD 0.25 0.5 1 2 D HR (95% CI) CALGB (n = 460) 0.56 (0.42 to 0.76) IFM (n = 614) 0.91 (0.72 to 1.15) GIMEMA (n = 134) 188 0.79 (0.58 to 1.06) 0.72 (0.37 to 1.38) 415 0.73 (0.58 to 0.91) Pooled (N = 1,208) 0.75 (0.63 to 0.90) 4 0.25 0.5 HR Favors Len Favors Placebo/ Maintenance Observation 1 2 HRǁ Favors Len Favors Placebo/ Maintenance Observation Fig 2. Overall survival (OS) analysis (intent-to-treat population). (A) Kaplan-Meier estimates of OS. (B) Hazard ratios (HRs) for OS by subgroup. (C) HRs for OS by prior induction subgroup. (D) HRs for OS by individual study. (*) Age at random assignment was available or used for the Cancer and Leukemia Group B (CALGB) 100104 study19 and the Intergroupe Francophone du Myélome (IFM) 2005-02 study20. Only age at diagnosis was available for the Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) RV-MM-PI-209 study2. (†) The International Staging System (ISS) stage was based on b2-microglobulin and albumin at diagnosis for the GIMEMA and IFM studies and at registration for the CALGB study. (‡) Upon central review, four patients did not meet the criteria for stable disease (SD). (§) All patients in the GIMEMA study received lenalidomide-based induction, which could be used in combination with any other drug. The size of each blue box corresponds to the size of the individual study. The CI is a function of the overall sample size. ASCT, autologous stem-cell transplantation; CR, complete response; Len, lenalidomide; NR, not reached; PR, partial response; TD, thalidomide and dexamethasone; VAD, vincristine, doxorubicin, and dexamethasone; VD, bortezomib and dexamethasone; VGPR, very good partial response. lenalidomide maintenance versus placebo or observation. Frequencies of hematologic SPMs occurring before PD (5.3% and 0.8% for lenalidomide and placebo or observation, respectively) and before and after PD (6.1% and 2.8% for lenalidomide and placebo or observation, respectively) were reported for both groups. In the lenalidomide maintenance and placebo or observation groups, frequencies of solid tumor SPMs occurring before 3284 PD (5.8% and 2.0%, respectively) and before and after PD (7.3% and 4.2%, respectively) were also reported. The cumulative incidence curves for hematologic and solid tumor SPMs are shown in Figures 3A and 3B. Time to invasive SPMs occurring before PD or start of second-line therapy was shorter in the lenalidomide maintenance group versus the placebo or observation group (HR, 2.67; 95% CI, 1.54 to 4.62; P , .001), whereas time to PD or © 2017 by American Society of Clinical Oncology Downloaded from ascopubs.org by 52.73.204.196 on May 16, 2022 from 052.073.204.196 Copyright © 2022 American Society of Clinical Oncology. All rights reserved. JOURNAL OF CLINICAL ONCOLOGY Lenalidomide Maintenance After ASCT in Multiple Myeloma Table 3. Discontinuations as a Result of TEAEs (safety population) No. of Patients (%) CALGB TEAE $ 1 TEAE leading to discontinuation TEAEs leading to discontinuation ($ 1% of all patients)‡ Blood and lymphatic system disorder Neutropenia Thrombocytopenia General disorders and administration site conditions Adverse event not specified Neoplasms: benign, malignant, and unspecified§ Skin and subcutaneous tissue disorders Nervous system disorders GI disorders Diarrhea Infections and infestations Musculoskeletal and connective tissue disorders IFM* Pooled Len Maintenance (n = 224) Placebo (n = 221) Len Maintenance (n = 306) Placebo (n = 302) Len Maintenance (n = 530)† Placebo (n = 523)† 63 (28.1) 19 (8.6) 91 (29.7) 45 (14.9) 154 (29.1) 64 (12.2) 11 5 6 12 10 16 6 5 5 5 4 1 (4.9) (2.2) (2.7) (5.4) (4.5) (7.1) (2.7) (2.2) (2.2) (2.2) (1.8) (0.4) 4 0 1 5 4 3 1 3 0 0 0 1 (1.8) (0.5) (2.3) (1.8) (1.4) (0.5) (1.4) (0.5) 12 7 3 13 0 7 12 13 13 6 5 5 (3.9) (2.3) (1.0) (4.2) (2.3) (3.9) (4.2) (4.2) (2.0) (1.6) (1.6) 7 1 5 3 0 2 9 6 1 0 4 6 (2.3) (0.3) (1.7) (1.0) (0.7) (3.0) (2.0) (0.3) (1.3) (2.0) 23 12 9 25 10 23 18 18 18 11 9 6 (4.3) (2.3) (1.7) (4.7) (1.9) (4.3) (3.4) (3.4) (3.4) (2.1) (1.7) (1.1) 11 1 6 8 4 5 10 9 1 0 4 7 (2.1) (0.2) (1.1) (1.5) (0.8) (1.0) (1.9) (1.7) (0.2) (0.8) (1.3) NOTE. Safety population includes patients who received at least one dose of study drug. Abbreviations: CALGB, Cancer and Leukemia Group B; GIMEMA, Gruppo Italiano Malattie Ematologiche dell’Adulto; IFM, Intergroupe Francophone du Myélome; Len; lenalidomide; TEAE, treatment-emergent adverse event. *In the IFM study, data from two cycles of lenalidomide consolidation are included. †Data from the IFM and CALGB studies only. ‡System organ class presented with preferred terms nested below. §Includes cysts and polyps. second-line therapy was longer with lenalidomide maintenance versus placebo or observation (HR, 0.51; 95% CI, 0.45 to 0.59; P , .001; Fig 3C). The risk of developing PD was higher than the risk of developing an invasive SPM in both groups. In the lenalidomide maintenance and placebo or observation groups, the cumulative incidence rates of PD or second-line therapy were consistently higher than that of invasive SPM over time (Data Supplement). The time to death as a result of MM was significantly longer in the lenalidomide maintenance group versus the placebo or observation group (HR, 0.66; 95% CI, 0.53 to 0.81; P , .001; Fig 3D). For time to death as a result of SPM or adverse event, there were no differences between the two groups. DISCUSSION An improved PFS with lenalidomide maintenance versus placebo or observation after HDM and ASCT in patients with NDMM was previously reported in the three studies analyzed in this report.2,19,20 The studies were not powered for OS, and OS data were not mature at the time of their initial publications. One trial, the CALGB trial, showed an early significant improvement in OS with lenalidomide maintenance. As a result of the increased SPM incidence with lenalidomide maintenance versus placebo reported in two of the trials, the CALGB and IFM trials, it was important to understand the risks and benefits of long-term lenalidomide maintenance after HDM and ASCT for patients with NDMM. The meta-analysis was planned to demonstrate a 20-month improvement in median OS based on an estimated median OS of 70 months with placebo or observation, approximating an HR of 0.78. The OS analysis was planned before identifying studies for data collection. Primary-source patient data from the three studies jco.org meeting the prespecified inclusion criteria were analyzed. The three studies consisted of generally similar patient populations, study designs, and maintenance approaches. The aggregate patient population provided sufficient power for the OS end point. A limitation of this analysis is the small number of studies included. Nevertheless, the meta-analysis was adequately powered to detect a treatment effect and demonstrated that lenalidomide maintenance versus placebo or observation after HDM and ASCT significantly prolonged OS and reduced the risk of death by 25%. A 29.3-month PFS improvement was observed with lenalidomide maintenance versus placebo or observation on an ITT basis; these results are not adjusted for the crossover of placebo arm patients without PD in the CALGB study. The PFS2 benefit with lenalidomide maintenance versus placebo or observation indicated that lenalidomide maintenance did not induce PD resistant to salvage treatment. The PFS improvements observed with lenalidomide maintenance in each study were similar despite different dosing schedules (days 1 to 28 of a 28-day schedule for CALGB and IFM and days 1 to 21 of a 28-day schedule for GIMEMA). The recently presented results from the Myeloma XI trial demonstrated a similar PFS improvement with lenalidomide maintenance versus observation (HR, 0.47; 95% CI, 0.38 to 0.60) after ASCT using a treatment schedule of 21 days of treatment in a 28-day schedule.26 The PFS subgroup analyses consistently favored lenalidomide maintenance versus placebo or observation, with differences in the magnitude of benefit. For the OS subgroup analyses, the benefit with lenalidomide maintenance was heterogeneous. The OS benefit with lenalidomide maintenance was less pronounced for patients older than age 60 years and for women. Patients with ISS disease stage III did not experience an OS benefit. The risk of death was reduced by 30% and 37% with lenalidomide maintenance versus placebo or observation in patients achieving very good partial © 2017 by American Society of Clinical Oncology Downloaded from ascopubs.org by 52.73.204.196 on May 16, 2022 from 052.073.204.196 Copyright © 2022 American Society of Clinical Oncology. All rights reserved. 3285 B 1.00 Len maintenance Placebo/observation 0.80 HR, 2.03 (95% CI, 1.14 to 3.61) P = .015 0.60 0.40 0.20 0 12 24 36 48 60 72 84 96 Cumulative Incidence (1 – KM) A Cumulative Incidence (1 – KM) McCarthy et al 1.00 Len maintenance Placebo/observation 0.80 HR, 1.71 (95% CI, 1.04 to 2.80) P = .031 0.60 0.40 0.20 0 108 12 No. at risk: Len 586 maintenance Placebo/ 601 observation 559 558 512 525 463 420 469 428 366 251 340 248 139 38 119 1 28 24 36 48 60 72 84 96 108 Time to Solid Tumor SPM Onset (months) Time to Hematologic SPM Onset (months) 0 No. at risk: Len 586 maintenance Placebo/ 601 observation 554 506 456 413 361 251 136 35 0 558 520 462 417 328 241 117 28 0 Cumulative Incidence (1 – KM) C Len maintenance: time to invasive SPM before PD or second-line therapy HR, 2.67 (95% CI, 1.54 to 4.62) Placebo/observation: time to invasive SPM before PD or second-line therapy P < .001 Len maintenance: time to PD or second-line therapy Placebo/observation: time to PD or second-line therapy 1.0 HR, 0.51 (95% CI, 0.45 to 0.59) P < .001 0.8 0.6 0.4 0.2 0 12 24 36 48 60 72 84 96 108 65 12 0 Time to Event (months) No. at risk: Len maintenance: time to invasive SPM before PD or second-line therapy 586 Placebo/observation: time to invasive SPM before PD or second-line therapy 601 434 282 195 142 98 59 31 5 0 Len maintenance: time to PD or second-line 586 therapy Placebo/observation: time to PD or 601 second-line therapy 498 414 335 268 219 144 79 15 0 437 284 200 148 104 60 31 5 0 490 403 314 245 196 125 D Len maintenance: caused by MM Len maintenance: caused by SPM Len maintenance: caused by AE Placebo/observation: caused by MM Placebo/observation: caused by SPM Placebo/observation: caused by AE Patients (proportion) 1.0 0.8 0.6 Time to death caused by MM with Len maintenance v placebo/observation: HR, 0.66 (95% CI, 0.53 to 0.81); P < .001 0.4 0.2 0 10 20 30 40 50 60 70 80 90 100 110 120 Time to Death (months) No. at risk: Len maintenance: caused by MM 605 577 555 508 473 431 385 282 200 95 20 1 Len maintenance: caused by SPM 605 577 555 508 473 431 385 282 200 95 20 1 0 0 Len maintenance: caused by AE 605 577 555 508 473 431 385 282 200 95 20 1 0 Placebo/observation: caused by MM 603 569 542 505 459 425 351 270 174 71 10 0 Placebo/observation: caused by SPM 603 569 542 505 459 425 351 270 174 71 10 0 Placebo/observation: caused by AE 603 569 542 505 459 425 351 270 174 71 10 0 Fig 3. Second primary malignancy and mortality analyses. (A) Cumulative incidence curve of time to hematologic second primary malignancy (SPM) onset (as-treated population). Patients who were randomly assigned but not treated with lenalidomide maintenance are included in the control group. (B) Cumulative incidence of time to solid tumor SPM onset (as-treated population). Patients who were randomly assigned but not treated with lenalidomide maintenance are included in the control group. (C) Cumulative incidence curves of time to disease progression and time to invasive SPM onset before disease progression. (D) Kaplan-Meier (KM) curve of time to death by cause of death. AE, adverse event; Len, lenalidomide; MM, multiple myeloma; PD, progressive disease. 3286 © 2017 by American Society of Clinical Oncology Downloaded from ascopubs.org by 52.73.204.196 on May 16, 2022 from 052.073.204.196 Copyright © 2022 American Society of Clinical Oncology. All rights reserved. JOURNAL OF CLINICAL ONCOLOGY Lenalidomide Maintenance After ASCT in Multiple Myeloma response or complete response, respectively. The induction subgroup analyses for OS favored lenalidomide maintenance versus placebo or observation. The effect was less favorable in patients who received a thalidomide-containing induction regimen or a vincristine, doxorubicin, and dexamethasone induction regimen. A PFS benefit, but not an OS benefit was seen with lenalidomide maintenance versus placebo or observation in patients with high-risk cytogenetics. Only a small number of patients had adverse-risk cytogenetics (n = 92). The Myeloma XI trial demonstrated improved PFS with lenalidomide maintenance versus observation in patients with high-risk cytogenetics, which included patients who had and had not received ASCT as a result of eligibility. The data are not yet mature enough for an OS analysis.26 The heterogeneity analysis demonstrated that all three studies contributed to the positive results of the meta-analysis. The HRs for each study are consistent with an OS improvement with lenalidomide maintenance versus placebo or observation. The quantitative heterogeneity results from the differences in magnitude of the treatment effect among the studies, particularly between the CALGB and IFM studies. Possible reasons for this heterogeneity include differences in and incomplete data for some patient demographics, different induction regimens, number of ASCTs, consolidation therapy after ASCT in the IFM study, discontinuation of lenalidomide maintenance before PD in the IFM study, crossover from placebo to lenalidomide maintenance in the CALGB study for patients without progression, and differences in frequency and type of second-line therapy. There were differences in the length of maintenance therapy in the three studies. The IFM study stopped lenalidomide maintenance at a mean duration of approximately 2 years. For the IFM study patients who stopped lenalidomide maintenance without progression (n = 119) the mean duration of maintenance was 3.3 years. The mean durations of maintenance in the CALGB and GIMEMA studies were 2.5 and 3 years, respectively. The proportions of patients on lenalidomide maintenance across the three studies are similar in the treatment duration categories of $ 1, $ 2, and $ 3 years. The cessation of lenalidomide maintenance in the IFM study is the primary reason for the smaller percentage of patients on lenalidomide maintenance at $ 4 years compared with the other studies. These duration differences may have influenced the magnitude of improvement in PFS, OS, and PFS2 but did not seem to reduce salvage treatment efficacy after PD. A recent retrospective analysis showed a correlation between length of lenalidomide maintenance therapy after ASCT and length of OS in patients with NDMM.27 None of these studies examined a predetermined maintenance duration. Future study designs may evaluate different lengths of maintenance therapy, particularly in patients who achieve minimal residual disease–negative status. In this analysis, the incidence rates of hematologic and solid tumor SPMs with lenalidomide maintenance were higher compared with placebo or observation. At a median follow-up time of 79.5 months, the rates of hematologic and solid tumor SPMs with lenalidomide maintenance before PD were 5.3% and 5.8%, jco.org respectively. These results are comparable to a previous metaanalysis of lenalidomide therapy in patients with NDMM that showed cumulative 5-year incidence rates of hematologic and solid tumor SPMs of 3.1% and 3.8%, respectively.28 The cumulative incidence rate of developing an SPM before PD is higher for patients who received lenalidomide maintenance, and the cumulative incidence rates of PD and death as a result of MM are higher for patients who received placebo or observation. Overall, the risk of developing PD is greater than that of developing an SPM. An important treatment goal for patients with NDMM is to achieve and maintain remission or long-term disease control.29,30 Maintenance therapy after ASCT can be considered a valid approach toward achieving long-term disease control, delaying time to relapse and second-line treatment, and prolonging survival. A previously published meta-analysis of RCTs comparing thalidomide- or lenalidomide-based maintenance versus thalidomideand lenalidomide-free maintenance or no maintenance therapy showed in stratified analyses that both maintenance therapies improve PFS, but not OS, in the transplantation setting.31 The study used published data from 2012 and 2014 of the same three trials in this analysis. The OS data were less mature, and the analysis did not use primary-source, patient-level data. This study demonstrates a statistically significant and clinically meaningful improvement in OS with lenalidomide maintenance. With new, highly active, triplet induction regimens enhancing depth and duration of response as well as ongoing studies evaluating the optimal timing of ASCT,32-36 the use of lenalidomide maintenance for transplantation-eligible patients can be considered a standard of care. The costs of maintenance therapy should be weighed against the costs of shorter survival, earlier progression, and earlier use of subsequent lines of therapies for patients without maintenance. Understanding the role of minimal residual disease detection and immune reconstitution after ASCT, as well as developing early end points as surrogates for long-term outcomes, should allow us to develop clinical strategies to further improve OS. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Disclosures provided by the authors are available with this article at jco.org. AUTHOR CONTRIBUTIONS Conception and design: All authors Collection and assembly of data: All authors Data analysis and interpretation: All authors Manuscript writing: All authors Final approval of manuscript: All authors Accountable for all aspects of the work: All authors © 2017 by American Society of Clinical Oncology Downloaded from ascopubs.org by 52.73.204.196 on May 16, 2022 from 052.073.204.196 Copyright © 2022 American Society of Clinical Oncology. All rights reserved. 3287 McCarthy et al REFERENCES 1. National Comprehensive Cancer Network: Clinical practice guidelines in oncology: Multiple myeloma (version 1.2017). https://www.nccn.org/ professionals/physician_gls/PDF/myeloma.pdf 2. Palumbo A, Cavallo F, Gay F, et al: Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med 371:895-905, 2014 3. McCarthy PL, Holstein SA: Role of stem cell transplant and maintenance therapy in plasma cell disorders. Hematology (Am Soc Hematol Educ Program) 2016:504-511, 2016 4. Attal M, Lauwers-Cances V, Hulin C, et al: Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med 376: 1311-1320, 2017 5. Borrello I: Can we change the disease biology of multiple myeloma? Leuk Res 36:S3-S12, 2012 (suppl 1) 6. Attal M, Harousseau JL, Stoppa AM, et al: A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome. N Engl J Med 335:91-97, 1996 7. Child JA, Morgan GJ, Davies FE, et al: Highdose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 348: 1875-1883, 2003 8. Attal M, Harousseau JL, Facon T, et al: Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med 349:2495-2502, 2003 9. Paiva B, Gutiérrez NC, Rosiñol L, et al: Highrisk cytogenetics and persistent minimal residual disease by multiparameter flow cytometry predict unsustained complete response after autologous stem cell transplantation in multiple myeloma. Blood 119:687-691, 2012 10. Rawstron AC, Child JA, de Tute RM, et al: Minimal residual disease assessed by multiparameter flow cytometry in multiple myeloma: Impact on outcome in the Medical Research Council Myeloma IX Study. J Clin Oncol 31:2540-2547, 2013 11. Martinez-Lopez J, Lahuerta JJ, Pepin F, et al: Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma. Blood 123:3073-3079, 2014 12. Harousseau JL, Avet-Loiseau H, Attal M, et al: Achievement of at least very good partial response is a simple and robust prognostic factor in patients with multiple myeloma treated with high-dose therapy: Long-term analysis of the IFM 99-02 and 99-04 trials. J Clin Oncol 27:5720-5726, 2009 13. Lahuerta JJ, Mateos MV, Martı́nez-López J, et al: Influence of pre- and post-transplantation responses on outcome of patients with multiple myeloma: Sequential improvement of response and achievement of complete response are associated with longer survival. J Clin Oncol 26:5775-5782, 2008 14. van de Velde HJ, Liu X, Chen G, et al: Complete response correlates with long-term survival and progression-free survival in high-dose therapy in multiple myeloma. Haematologica 92:1399-1406, 2007 15. Martinez-Lopez J, Blade J, Mateos MV, et al: Long-term prognostic significance of response in multiple myeloma after stem cell transplantation. Blood 118:529-534, 2011 16. Barlogie B, Anaissie E, Haessler J, et al: Complete remission sustained 3 years from treatment initiation is a powerful surrogate for extended survival in multiple myeloma. Cancer 113:355-359, 2008 17. Hoering A, Crowley J, Shaughnessy JD Jr, et al: Complete remission in multiple myeloma examined as time-dependent variable in terms of both onset and duration in Total Therapy protocols. Blood 114:1299-1305, 2009 18. Moreau P, Attal M, Facon T: Frontline therapy of multiple myeloma. Blood 125:3076-3084, 2015 19. McCarthy PL, Owzar K, Hofmeister CC, et al: Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 366:1770-1781, 2012 20. Attal M, Lauwers-Cances V, Marit G, et al: Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 366: 1782-1791, 2012 21. Palumbo A, Hajek R, Delforge M, et al: Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med 366:1759-1769, 2012 22. Benboubker L, Dimopoulos MA, Dispenzieri A, et al: Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med 371:906-917, 2014 23. Weber DM, Chen C, Niesvizky R, et al: Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 357:2133-2142, 2007 24. Dimopoulos M, Spencer A, Attal M, et al: Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 357: 2123-2132, 2007 25. Quach H, Ritchie D, Stewart AK, et al: Mechanism of action of immunomodulatory drugs (IMiDS) in multiple myeloma. Leukemia 24:22-32, 2010 26. Jackson GH, Davies FE, Pawlyn C, et al: Lenalidomide is a highly effective maintenance therapy in myeloma patients of all ages: Results of the phase III Myeloma XI study. Blood 128, 2016 (abstr 1143) 27. Mian I, Milton DR, Shah N, et al: Prolonged survival with a longer duration of maintenance lenalidomide after autologous hematopoietic stem cell transplantation for multiple myeloma. Cancer 122:3831-3837, 2016 28. Palumbo A, Bringhen S, Kumar SK, et al: Second primary malignancies with lenalidomide therapy for newly diagnosed myeloma: A metaanalysis of individual patient data. Lancet Oncol 15: 333-342, 2014 29. Palumbo A, Anderson K: Multiple myeloma. N Engl J Med 364:1046-1060, 2011 30. Stewart AK, Richardson PG, San-Miguel JF: How I treat multiple myeloma in younger patients. Blood 114:5436-5443, 2009 31. Wang Y, Yang F, Shen Y, et al: Maintenance therapy with immunomodulatory drugs in multiple myeloma: A meta-analysis and systematic review. J Natl Cancer Inst 108:djv342, 2015 32. Rajkumar SV: Doublets, triplets, or quadruplets of novel agents in newly diagnosed myeloma? Hematology (Am Soc Hematol Educ Program) 2012: 354-361, 2012 33. Dhakal B, Girnius S, Hari P: Recent advances in understanding multiple myeloma. F1000Research, 2016 doi:10.12688/f1000research.8777.1 34. Richardson PG, Weller E, Lonial S, et al: Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 116:679-686, 2010 35. Jakubowiak AJ, Dytfeld D, Griffith KA, et al: A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood 120:1801-1809, 2012 36. Moreau P, San Miguel J, Sonneveld P, et al: Multiple myeloma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 10.1093/annonc/mdx096 [epub ahead of print on April 27, 2017] Affiliations Philip L. McCarthy, Roswell Park Cancer Institute, Buffalo, NY; Sarah A. Holstein, University of Nebraska Medical Center, Omaha, NE; Maria Teresa Petrucci, University La Sapienza; Antonio Palumbo, Takeda Italia, Rome; Patrizia Tosi, Rimini Hospital, Rimini; Sara Bringhen and Francesca Gay, University of Torino, Torino; Pellegrino Musto, Cancer Institute for Research and Care and The Referral Cancer Center of Basilicata, Rionero in Vulture, Italy; Paul G. Richardson and Kenneth C. Anderson, Dana-Farber Cancer Institute, Boston, MA; Cyrille Hulin and Gerald Marit, Bordeaux Centre Hospitalier Universitaire, Bordeaux; Denis Caillot, Dijon University Hospital Center, Dijon; Philippe Moreau, University Hospital Hôtel-Dieu, Nantes; Michel Attal, Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France; Sin-Ho Jung, Duke University, Durham, NC; and Zhinuan Yu, Benjamin Winograd, and Robert D. Knight, Celgene Corporation, Summit, NJ. Support Supported by Celgene Corporation. The Cancer and Leukemia Group B 100104 trial was funded by the National Cancer Institute and National Heart, Lung, and Blood Institute and conducted by the Alliance for Clinical Trials in Oncology, Eastern Cooperative Oncology Group, and Blood and Marrow Transplant Clinical Trials Network. The Gruppo Italiano Malattie Ematologiche dell’Adulto RV-MM-PI209 trial was funded by Celgene Corporation. The Intergroupe Francophone du Myélome 2005-02 trial was funded by the Programme Hospitalier de Recherche Clinique, the Swiss Group for Clinical Cancer Research, and a grant from Celgene Corporation. 3288 © 2017 by American Society of Clinical Oncology Downloaded from ascopubs.org by 52.73.204.196 on May 16, 2022 from 052.073.204.196 Copyright © 2022 American Society of Clinical Oncology. All rights reserved. JOURNAL OF CLINICAL ONCOLOGY Lenalidomide Maintenance After ASCT in Multiple Myeloma Prior Presentation Presented in part at the 52nd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 3-7, 2016, and the 21st Congress of the European Hematology Association, Copenhagen, Denmark, June 9-12, 2016. nnn ASCO University: Your Home for the Latest Oncology Education ASCO University, the society’s online educational home for oncology care professionals, offers lifelong learning by providing practice resources and educational opportunities for those in all oncology sub-specialties. Content is updated monthly. Visit university.asco.org regularly for new courses. jco.org © 2017 by American Society of Clinical Oncology Downloaded from ascopubs.org by 52.73.204.196 on May 16, 2022 from 052.073.204.196 Copyright © 2022 American Society of Clinical Oncology. All rights reserved. 3289 McCarthy et al AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Lenalidomide Maintenance After Autologous Stem-Cell Transplantation in Newly Diagnosed Multiple Myeloma: A Meta-Analysis The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc. Philip L. McCarthy Honoraria: Celgene, Bristol-Myers Squibb, Sanofi, Takeda, The Binding Site, Karyopharm Therapeutics Consulting or Advisory Role: Celgene, Janssen, Bristol-Myers Squibb, Sanofi, Karyopharm Therapeutics Research Funding: Celgene (Inst) Denis Caillot No relationship to disclose Francesca Gay Honoraria: Celgene, Janssen, Takeda, Bristol-Myers Squibb, Amgen Consulting or Advisory Role: Amgen, Roche, Takeda, Celgene, Seattle Genetics Sarah A. Holstein Consulting or Advisory Role: Celgene, Takeda Research Funding: Celgene (Inst) Travel, Accommodations, Expenses: Celgene Philippe Moreau Honoraria: Celgene, Takeda, Novartis, Janssen-Cilag, Amgen Consulting or Advisory Role: Celgene, Takeda, Janssen, Novartis, Amgen Maria Teresa Petrucci Honoraria: Janssen-Cilag, Celgene, Bristol-Myers Squibb, Takeda, Amgen Gerald Marit Travel, Accommodations, Expenses: Celgene, Janssen-Cilag, The Binding Site Paul G. Richardson Consulting or Advisory Role: Celgene Research Funding: Celgene, Millennium Sin-Ho Jung No relationship to disclose Cyrille Hulin Honoraria: Celgene, Amgen, Bristol-Myers Squibb, Novartis, JanssenCilag, Takeda Zhinuan Yu Employment: Celgene Stock or Other Ownership: Celgene Patrizia Tosi No relationship to disclose Benjamin Winograd Employment: Celgene Stock or Other Ownership: Celgene Sara Bringhen Honoraria: Celgene, Janssen-Cilag, Bristol-Myers Squibb Consulting or Advisory Role: Amgen, Mundipharma, Karyopharm Therapeutics Robert D. Knight Employment: Celgene Stock or Other Ownership: Celgene Pellegrino Musto Honoraria: Celgene, Janssen-Cilag, Sanofi, Amgen, Takeda, Bristol-Myers Squibb Kenneth C. Anderson Consulting or Advisory Role: Celgene, Millennium, Gilead Sciences, Bristol-Myers Squibb Patents, Royalties, Other Intellectual Property: C4 Therapeutics, Oncopep, Acetylon Antonio Palumbo Employment: Takeda Honoraria: Genmab, Janssen-Cilag, Takeda Consulting or Advisory Role: Genmab, Janssen-Cilag, Takeda Research Funding: Genmab (Inst), Janssen-Cilag (Inst), Takeda (Inst) Michel Attal No relationship to disclose © 2017 by American Society of Clinical Oncology Downloaded from ascopubs.org by 52.73.204.196 on May 16, 2022 from 052.073.204.196 Copyright © 2022 American Society of Clinical Oncology. All rights reserved. JOURNAL OF CLINICAL ONCOLOGY Lenalidomide Maintenance After ASCT in Multiple Myeloma Acknowledgment We thank Kristina Hernandez and Peter Simon for medical writing assistance, which was sponsored by Celgene Corporation. jco.org © 2017 by American Society of Clinical Oncology Downloaded from ascopubs.org by 52.73.204.196 on May 16, 2022 from 052.073.204.196 Copyright © 2022 American Society of Clinical Oncology. All rights reserved.