Ixazomib as Postinduction Maintenance for original reports Patients With Newly Diagnosed Multiple Myeloma Not Undergoing Autologous Stem Cell Transplantation: The Phase III TOURMALINE-MM4 Trial Meletios A. Dimopoulos, MD1; Ivan Špička, MD2; Hang Quach, MD3; Albert Oriol, MD4; Roman Hájek, MD5; Mamta Garg, MD6; Meral Beksac, MD7; Sara Bringhen, MD8; Eirini Katodritou, MD9; Wee-Joo Chng, MD10; Xavier Leleu, MD11; Shinsuke Iida, MD12; Marı́a-Victoria Mateos, MD13; Gareth Morgan, MD14; Alexander Vorog, MD15; Richard Labotka, MD15; Bingxia Wang, PhD15; Antonio Palumbo, MD15; and Sagar Lonial, MD16; on behalf of the TOURMALINE-MM4 study group abstract PURPOSE Maintenance therapy prolongs progression-free survival (PFS) in patients with newly diagnosed multiple myeloma (NDMM) not undergoing autologous stem cell transplantation (ASCT) but has generally been limited to immunomodulatory agents. Other options that complement the induction regimen with favorable toxicity are needed. PATIENTS AND METHODS The phase III, double-blind, placebo-controlled TOURMALINE-MM4 study randomly assigned (3:2) patients with NDMM not undergoing ASCT who achieved better than or equal to partial response after 6-12 months of standard induction therapy to receive the oral proteasome inhibitor (PI) ixazomib or placebo on days 1, 8, and 15 of 28-day cycles as maintenance for 24 months. The primary endpoint was PFS since time of randomization. RESULTS Patients were randomly assigned to receive ixazomib (n 5 425) or placebo (n 5 281). TOURMALINE- MM4 met its primary endpoint with a 34.1% reduction in risk of progression or death with ixazomib versus placebo (median PFS since randomization, 17.4 v 9.4 months; hazard ratio [HR], 0.659; 95% CI, 0.542 to 0.801; P , .001; median follow-up, 21.1 months). Ixazomib significantly benefitted patients who achieved complete or very good partial response postinduction (median PFS, 25.6 v 12.9 months; HR, 0.586; P , .001). With ixazomib versus placebo, 36.6% versus 23.2% of patients had grade $ 3 treatment-emergent adverse events (TEAEs); 12.9% versus 8.0% discontinued treatment because of TEAEs. Common any-grade TEAEs included nausea (26.8% v 8.0%), vomiting (24.2% v 4.3%), and diarrhea (23.2% v 12.3%). There was no increase in new primary malignancies (5.2% v 6.2%); rates of on-study deaths were 2.6% versus 2.2%. CONCLUSION Ixazomib maintenance prolongs PFS with no unexpected toxicity in patients with NDMM not undergoing ASCT. To our knowledge, this is the first PI demonstrated in a randomized clinical trial to have single- ASSOCIATED agent efficacy for maintenance and is the first oral PI option in this patient population. CONTENT J Clin Oncol 38:4030-4041. © 2020 by American Society of Clinical Oncology Data Supplement Creative Commons Attribution Non-Commercial No Derivatives 4.0 License Protocol Author affiliations and support INTRODUCTION immunomodulatory drugs, and monoclonal antibodies information (if Treatment for multiple myeloma (MM) is shifting in- are backbones of therapy for MM.7 However, there are applicable) appear creasingly to maintenance and continuous therapy, no approved maintenance or continuous therapy at the end of this options with PIs for initial therapy.8,9 article. which improves outcomes versus fixed-duration Accepted on August treatment followed by a remission period. 1-3 Real- Maintenance therapy prolongs PFS in the post- 26, 2020 and world data suggest that, at relapse, approximately transplantation and nontransplantation settings, and published at one third of patients never receive second-line overall survival (OS) when used post-transplantation.10-12 ascopubs.org/journal/ treatment,4,5 highlighting the importance of maximiz- To date, only lenalidomide is approved as post- jco on October 6, 2020: DOI https://doi. ing progression-free survival (PFS) with initial therapy transplantation maintenance therapy.13 There are org/10.1200/JCO.20. and the need for tolerable, active treatment options for currently no agents specifically approved as main- 02060 long-term administration.6 Proteasome inhibitors (PIs), tenance after any standard-of-care induction therapy 4030 Volume 38, Issue 34 Downloaded from ascopubs.org by 95.127.176.247 on February 17, 2021 from 095.127.176.247 Copyright © 2021 American Society of Clinical Oncology. All rights reserved. Ixazomib Maintenance in Patients With Multiple Myeloma Not Undergoing Stem Cell Transplantation CONTEXT Key Objective Does the oral proteasome inhibitor ixazomib improve progression-free survival (PFS) in patients with newly diagnosed multiple myeloma (NDMM) not undergoing autologous stem cell transplantation when used as maintenance therapy after best response to any standard-of-care induction? Knowledge Generated Treatment with weekly ixazomib maintenance resulted in a statistically significant and clinically meaningful improvement in PFS since randomization, with an 8-month increase in the median, and demonstrated PFS benefits in prespecified patient subgroups, including a statistically significant benefit in patients who achieved complete or very good partial responses to initial therapy, and benefits in patients with stage IIII disease, patients aged $ 75 years, and patients with expanded high-risk cytogenetics. Ixazomib maintenance had a tolerable safety profile with no increase in health care use or impact on patients’ self-reported quality of life as measured by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-Core 30 and EORTC QLQ-MY20 questionnaires. Relevance To our knowledge, ixazomib is the first induction-agnostic maintenance option investigated for transplantation-ineligible patients with NDMM and represents a valuable treatment option in this setting. for patients not undergoing autologous stem cell trans- and who achieved at least a partial response (PR) as their plantation (ASCT). These patients may receive continuous best response after 6-12 months of any standard-of-care treatment with one or more agents received as induction, such induction therapy, were eligible. Patients required an as lenalidomide9,14,15 and/or daratumumab.8,16 In routine Eastern Cooperative Oncology Group performance status of clinical practice, treatment duration may be limited because of 0 to 2 and documented initial disease state, initial therapy toxicity and route of administration.6,17 More tolerable and and response, and cytogenetics and International Staging convenient options are required for this generally elderly System (ISS) disease stage assessments at diagnosis (Data population, who may not be eligible for transplantation because Supplement). Eligible patients were required to be ran- of age or presence of comorbidities.18 domly assigned # 60 days after the last dose of induction The oral PI ixazomib is approved in combination with therapy. lenalidomide-dexamethasone for the treatment of patients Procedures with MM who have received one prior therapy.19 Ixazomib as post-transplantation maintenance therapy prolongs PFS Using centralized randomization through an interactive versus placebo,20 with limited cumulative toxicity or impact voice/web response system (Data Supplement), patients on quality of life (QoL).20,21 We report the efficacy and safety were randomly assigned 3:2 to receive either oral ixazomib of ixazomib as maintenance therapy in transplantation- 3 mg or matching placebo on days 1, 8, and 15 of 28-day ineligible patients after standard-of-care induction therapy. cycles. The dose was increased to 4 mg from cycle 5 if tolerated during cycles 1-4 (Data Supplement). Random- ization was stratified by induction regimen (PI-containing v PATIENTS AND METHODS non-PI therapy); preinduction ISS disease stage (I or II v III); Trial Design and Patients age at randomization (, 75 v $ 75 years); and response to In this randomized, double-blind, placebo-controlled, initial therapy at screening (complete response [CR] or very phase III trial, patients were randomly assigned from April 23, good partial response [VGPR] v PR). Patients continued 2015, through October 8, 2018, at 187 sites in 34 countries treatment for approximately 24 months (if no treatment (Data Supplement, online only). The trial was conducted in delays, equivalent to 26 cycles, to the nearest complete accordance with the principles of the Declaration of cycle) or until progressive disease (PD) or unacceptable Helsinki, the International Conference on Harmonization toxicity, whichever occurred first. Dose adjustments for Good Clinical Practice guidelines, and appropriate regu- toxicities were permitted using protocol-specified dose- latory requirements. Local independent ethics committees modification guidelines. or institutional review boards at each site approved the protocol, which is available in the Data Supplement. All Outcomes and Assessments patients provided written informed consent. The primary endpoint was PFS, defined as time since Adults with a confirmed diagnosis of symptomatic MM per random assignment to first documentation of PD (per in- International Myeloma Working Group (IMWG) criteria22 dependent review committee [IRC] evaluation) or death as who were ineligible for, or did not wish to receive, ASCT a result of any cause. The key secondary endpoint was OS. Journal of Clinical Oncology 4031 Downloaded from ascopubs.org by 95.127.176.247 on February 17, 2021 from 095.127.176.247 Copyright © 2021 American Society of Clinical Oncology. All rights reserved. Dimopoulos et al Secondary and exploratory endpoints are listed in the Data treatment period and through 30 days after the last dose of Supplement. the study drug and graded according to the National Cancer Institute’s Common Terminology Criteria for Ad- Patient evaluations and follow-up are summarized in the verse Events, version 4.03. For more details on assess- Data Supplement. Response was assessed on day 1 of ments, see the Data Supplement. every treatment cycle and every 4 weeks during the PFS follow-up period until PD. Response and PD were evaluated by an IRC blinded to both treatment assignment and in- Statistical Analysis vestigator assessment of response; assessments were The study used a closed sequential testing procedure for based on central laboratory M-protein results, plus local the primary (PFS) and key secondary (OS) endpoints, in bone marrow and imaging data, using IMWG 2011 crite- this order. Two interim analyses (IAs), plus a final analysis, ria.23 Adverse events (AEs) were assessed throughout the were planned to test OS; the first IA, reported here, was the Enrollment Patients assessed for eligibility (n = 974) Ineligible patients (n = 268) Patients enrolled (n = 706) Patients randomly assigned (n = 706) Ixazomib maintenance Placebo maintenance (n = 425) (n = 281) Allocation Allocated to receive ixazomib maintenance therapy (n = 425) Allocated to receive placebo maintenance therapy (n = 281) Received ixazomib maintenance therapy (n = 423) Received placebo maintenance therapy (n = 279) Did not receive ixazomib maintenance therapy (n = 2) Did not receive placebo maintenance therapy (n = 2) Withdrawal by patient (n = 2) Withdrawal by patient (n = 2) Treatment Ongoing on treatment (n = 83) Ongoing on treatment (n = 43) Completed maximum number of cycles per protocol (n = 66) Completed maximum number of cycles per protocol (n = 30) Discontinued intervention (n = 276) Discontinued intervention (n = 208) Progressive disease (n = 188) Progressive disease (n = 174) Adverse event (n = 47) Adverse event (n = 15) Withdrawal of consent (n = 9) Withdrawal of consent (n = 8) Other (n = 32) Other (n = 11) Follow-Up Patients in follow-up (n = 203) Patients in follow-up (n = 152) Patients lost to follow-up (n = 6) Patients lost to follow-up (n = 4) Patients withdrew (n = 42) Patients withdrew (n = 29) Analysis Patients included in intention-to-treat efficacy analysis (n = 425) Patients included in intention-to-treat efficacy analysis (n = 281) Patients included in safety analysis population (n = 426) Patients included in safety analysis population (n = 276) Includes patients allocated to placebo who erroneously (n = 3) Patients excluded from the safety analysis population: (n = 5) received a single dose of ixazomib maintenance therapy Did not receive placebo maintenance therapy (n = 2) Patients excluded from the safety analysis population (n = 2) Patients allocated to placebo who erroneously received (n = 3) Did not receive ixazomib maintenance therapy (n = 2) a single dose of ixazomib maintenance therapy FIG 1. CONSORT diagram. 4032 © 2020 by American Society of Clinical Oncology Volume 38, Issue 34 Downloaded from ascopubs.org by 95.127.176.247 on February 17, 2021 from 095.127.176.247 Copyright © 2021 American Society of Clinical Oncology. All rights reserved. Ixazomib Maintenance in Patients With Multiple Myeloma Not Undergoing Stem Cell Transplantation TABLE 1. Baseline Characteristics of Patients in the Intention-to-Treat Population primary and only analysis of PFS. See the Data Supplement Ixazomib Placebo for detailed statistical analysis methodology. At this anal- Characteristic (n 5 425) (n 5 281) ysis, the study had 90% power to detect a hazard ratio (HR) Age, years of 0.71 (two-sided log-rank test, two-sided alpha of .04) for Median (range) 72 (42-89) 73 (52-90) PFS in the intention-to-treat-population. Additionally, PFS , 65 39 (9.2) 29 (10.3) was tested in parallel in three prespecified subgroups per stratification variables: patients with preinduction ISS stage $ 65 and , 75 226 (53.2) 142 (50.5) III disease, patients aged $ 75 years, and patients who $ 75 160 (37.6) 110 (39.1) achieved CR or VGPR with initial therapy. Subgroup testing Male sex 222 (52.2) 155 (55.2) for PFS was conducted using the remaining alpha (.01) and Racea the Hochberg procedure for multiplicity correction (Data White 330 (77.6) 227 (80.8) Supplement). The study was not powered for statistical testing in other prespecified subgroups. The O’Brien- Asian 63 (14.8) 39 (13.9) Fleming alpha spending function (Lan-Demets method24) Black or African American 15 (3.5) 5 (1.8) was used to calculate the significance boundary for OS on Type of myeloma at initial diagnosis the basis of the observed number of deaths at each IA. All Immunoglobulin G 252 (59.3) 174 (61.9) other efficacy endpoints were tested at a two-sided alpha Immunoglobulin A 102 (24.0) 67 (23.8) level of .05. Analysis populations are defined in the Data Supplement. Light chain 62 (14.6) 36 (12.8) b Other 9 (2.1) 4 (1.4) RESULTS ISS disease stage at initial diagnosisc Patients I 112 (26.4) 66 (23.5) II 165 (38.8) 114 (40.6) A total of 706 patients with newly diagnosed MM (NDMM) were enrolled (Fig 1), 425 in the ixazomib arm and 281 in III 148 (34.8) 101 (35.9) the placebo arm. Baseline patient demographics and d ECOG PS at study entry disease characteristics, including prior induction treat- 0 213 (50.1) 147 (52.3) ment, were well balanced between groups (Table 1; Data 1 193 (45.4) 120 (42.7) Supplement). Overall median age at study entry was 2 18 (4.2) 14 (5.0) 73 years, with 38.2% of patients aged $ 75 years; 35.3% of e patients had ISS stage III disease, 82.3% received a PI and Frailty status 32.7% received an immunomodulatory drug as part of their Fit 172 (40.5) 112 (39.9) induction regimen, and 62.0% were in CR or VGPR at Unfit 147 (34.6) 98 (34.9) study entry. Frail 102 (24.0) 68 (24.2) Efficacy Creatinine clearance at study entry (mL/min)f At data cutoff (August 12, 2019), with a median overall , 30 8 (1.9) 3 (1.1) follow-up for PFS of 21.1 months, there was a significant 34.1% reduction in risk of progression or death in the 30 to , 60 148 (34.8) 104 (37.0) ixazomib versus placebo group (HR, 0.659; 95% CI, 0.542 60 to , 90 184 (43.3) 108 (38.4) to 0.801; P , .001); median PFS since randomization was $ 90 85 (20.0) 65 (23.1) 17.4 months (95% CI, 14.8 to 20.3 months) versus Cytogenetic features 9.4 months (95% CI, 8.5 to 11.5 months; Fig 2A). When High-risk cytogenetic 74 (17.4) 48 (17.1) landmarked to the date of induction therapy, median total abnormalitiesg PFS time since start of induction was 26.3 versus Expanded high-risk 150 (35.3) 91 (32.4) 20.3 months in the ixazomib versus placebo group cytogenetic abnormalitiesh (Table 2). In the prespecified subgroups, there was a sta- Elevated lactate dehydrogenase 57 (13.4) 38 (13.5) tistically significant improvement in PFS since randomi- at study entry zation with ixazomib versus placebo in patients who achieved CR or VGPR with initial therapy (HR, 0.586; Evidence of lytic bone disease 203 (47.8) 141 (50.2) at study entry 95% CI, 0.449 to 0.765; P , .001). Clinical benefits were observed in patients with ISS stage III disease (HR, 0.695; (continued on following page) 95% CI, 0.499 to 0.967; P 5 .030) and patients Journal of Clinical Oncology 4033 Downloaded from ascopubs.org by 95.127.176.247 on February 17, 2021 from 095.127.176.247 Copyright © 2021 American Society of Clinical Oncology. All rights reserved. Dimopoulos et al TABLE 1. Baseline Characteristics of Patients in the Intention-to-Treat Population aged $ 75 years (HR, 0.738; 95% CI, 0.537 to 1.014; P 5 (continued) .060; Table 2). PFS benefit in other patient subgroups is Ixazomib Placebo summarized in Figure 2B. Characteristic (n 5 425) (n 5 281) Median time to progression was 17.8 versus 9.6 months Induction regimen containingi with ixazomib versus placebo, and response improvements PI 351 (82.6) 230 (81.9) during maintenance were seen in 14.6% versus 8.2% of Bortezomib 346 (81.4) 228 (81.1) patients (Table 2). PFS2 and OS data were not mature at Immunomodulatory drug 137 (32.2) 94 (33.5) the time of this analysis. The study remains blinded; follow- Thalidomide 92 (21.6) 63 (22.4) up for PFS2 and OS continues. Lenalidomide 47 (11.1) 32 (11.4) Treatment Exposure and Safety PI plus immunomodulatory 66 (15.5) 44 (15.7) drug The safety population included 426 and 276 patients in the ixazomib and placebo groups, respectively (Fig 1). Treat- Common regimens ($ 5% overall) ment exposure data are summarized in Table 3. At data VMP 117 (27.5) 88 (31.3) cutoff, patients had received a median of 13 (1 to 26) and VCd 112 (26.4) 75 (26.7) 12 (1 to 26) treatment cycles in the ixazomib and placebo VTd 27 (6.4) 14 (5.0) groups, respectively, 16.0% and 10.1% of patients had Rd 20 (4.7) 16 (5.7) completed all protocol-specified cycles, and 19.5% and CTd 21 (4.9) 14 (5.0) 15.3% were ongoing; 70.7% and 78.3% of patients dose- escalated from the starting dose of 3 mg to 4 mg, Response at study entryi respectively. CR 96 (22.6) 62 (22.1) In the ixazomib versus placebo group, 36.6% versus VGPR 168 (39.5) 112 (39.9) 23.2% of patients had grade $ 3 treatment-emergent PR 161 (37.9) 107 (38.1) AEs (TEAEs), 22.1% versus 16.7% had serious TEAEs, Median time from start of 9.5 (5.6-15.0) 9.4 (6.3-14.8) and 30.8% versus 5.1% had a dose reduction and induction to first 12.9% versus 8.0% discontinued because of TEAEs maintenance dose (Table 3). TEAEs for which the incidence was $ 5% higher (range), months with ixazomib versus placebo included nausea (26.8% v NOTE. Data are No. (%) unless otherwise indicated. See the Data Supplement for 8.0%), rash (25.6% v 10.5%), vomiting (24.2% v 4.3%), detailed baseline characteristics. diarrhea (23.2% v 12.3%), peripheral neuropathy (19.5% v Abbreviations: CR, complete response; CTd, cyclophosphamide-thalidomide- 10.9%), and pyrexia (11.3% v 5.1%; Table 4). Most TEAEs dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance were grade 1 or 2 severity, with rates of grade $ 3 events status; ISS, International Staging System; PI, proteasome inhibitor; PR, partial being # 3% for all individual TEAEs except pneumonia response; Rd, lenalidomide-dexamethasone; VCd, bortezomib-cyclophosphamide- (3.8% grade 3; n 5 16; ixazomib group). There was no dexamethasone; VGPR, very good partial response; VMP, bortezomib- evidence of cumulative toxicity over the course of treat- melphalan-prednisone; VTd, bortezomib-thalidomide-dexamethasone. a Additional categories reported for race are summarized in a footnote in the Data ment. Rates of cardiac arrhythmias, heart failure, hypo- Supplement. tension, liver impairment, and renal impairment were all low b Other categories are summarized in a footnote in the Data Supplement. and similar between groups (Table 4). Nine patients (2.1%) c Data shown are per patient-level data and not per data reported for in the ixazomib group had grade $ 3 events of renal im- randomization stratification. pairment (considered unrelated to the study drug in six); d Data missing for one patient in the ixazomib arm. three events resolved (two without drug interruption, one e Patients’ frailty status was classified as fit, unfit, or frail on the basis of four after dose delay), three resulted in discontinuation, and the components: age, the Katz Index of Independence in Activities of Daily Living, the one grade 5 event was considered unrelated to the study Lawton Instrumental Activities of Daily Living Scale, and the Charlson Comorbidity drug. Of these patients, three had preexisting kidney dis- Index Scoring System. Frailty status was reported as missing in four patients (0.9%) ease, including the patient who died. The overall rate of in the ixazomib arm and three patients (1.1%) in the placebo arm. f herpes zoster was 3.1% with ixazomib and 0.7% with Data missing for one patient in the placebo arm. g High-risk cytogenetic abnormalities were del(17p), t(4;14), and t(14;16). If all placebo; in patients receiving antiviral prophylaxis, rates three abnormalities were unknown, indeterminate, or missing, the patient was were 0.4% and 0%, respectively (Table 4). At a median called unclassifiable. There was no cutoff for defining the presence of del(17p). All follow-up of 2 years, there was no difference in the rate of cytogenetic evaluations were performed locally according to local standards. See new primary malignancies (Table 4). the Data Supplement for additional details. h Changes in mean Global Health Status/QoL score on the Expanded high-risk cytogenetic abnormalities comprised the high-risk European Organization for Research and Treatment of cytogenetic abnormalities plus amplification of 1q21. See the Data Supplement for additional details. Cancer Quality of Life Questionnaire Core-30 are shown in i Per investigator. the Data Supplement. Scores were similar between groups 4034 © 2020 by American Society of Clinical Oncology Volume 38, Issue 34 Downloaded from ascopubs.org by 95.127.176.247 on February 17, 2021 from 095.127.176.247 Copyright © 2021 American Society of Clinical Oncology. All rights reserved. Ixazomib Maintenance in Patients With Multiple Myeloma Not Undergoing Stem Cell Transplantation A 1.0 No. of Median Patients Events PFS FIG 2. Kaplan-Meier analysis of progression-free (months) 0.8 Ixazomib 425 228 17.4 survival (PFS) by independent review (A) in the Placebo 281 198 9.4 intention-to-treat population and (B) by pre- PFS (probability) HR (95% CI), 0.659 (0.542 to 0.801) specified patient subgroups. Stratified log-rank Log-rank test P < .001 0.6 Median follow-up, 21.1 months tests and Cox models were used for interarm com- parisons. Some subgroup data are not shown be- cause of small patient numbers. (*) Data per 0.4 39.2% (95% Cl, 33.6% to 44.7%) stratification variables. (†) Data per individual patient- Ixazomib level clinical data after medical review. (‡) High-risk cytogenetic abnormalities were del(17p), t(4;14), and 0.2 24.1% (95% Cl, 18.5% to 30.2%) t(14;16). See the Data Supplement for additional details. (¶) Expanded high-risk cytogenetic abnor- Placebo malities comprised the high-risk cytogenetic abnor- 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 malities plus amplification of 1q21. See the Data Supplement for additional details. CR, complete re- Time Since Random Assignment (months) sponse; HR, hazard ratio; IMiD, immunomodulatory No. at risk: Ixazomib 425 342 283 255 201 166 123 90 69 46 31 23 17 9 4 0 0 drug; ISS, International Staging System; PI, proteasome Placebo 281 218 183 142 102 67 54 42 32 20 16 11 9 4 3 1 0 inhibitor; PR, partial response; VGPR, very good partial response. at study entry and were maintained in both groups during treatment settings.21,27,28 TOURMALINE-MM4 (Clinical- the protocol-defined treatment period. Trials.gov identifier: NCT02312258) findings also support the Health care resource use (HRU) during treatment is significant PFS benefit seen with ixazomib versus placebo as summarized in the Data Supplement. Ixazomib did not post-transplantation maintenance therapy in the TOURMA- result in additional HRU (hospitalizations, emergency room LINE-MM3 trial.20 Together, these studies demonstrate the stays, and outpatient visits). utility and prolonged activity of oral, once-weekly ixazomib maintenance. DISCUSSION In the context of current therapy, the comparison versus placebo is a limitation of TOURMALINE-MM4; however, Ixazomib maintenance after standard-of-care induction at the time of study design, there were no approved treatment resulted in a statistically significant and clinically or standard-of-care maintenance therapies in non- meaningful25 34.1% reduction in the risk of progression or transplantation NDMM and thus no clear comparator to use death since the time of randomization compared with instead of placebo. Furthermore, current standard-of-care placebo, with an 8-month increase in median PFS. Addi- maintenance may vary among regions. Nevertheless, it is tionally, a statistically significant benefit was demonstrated well established that lenalidomide provides a significant in patients who achieved CR or VGPR with initial therapy. improvement in PFS after induction therapy in transplantation- Outcomes since randomization favoring ixazomib were ineligible patients. In the Myeloma XI trial,10 lenalidomide seen in patients with ISS stage III disease and patients aged improved PFS since maintenance randomization versus ob- $ 75 years. In the prespecified subgroups of patients with servation.10 This study differs from TOURMALINE-MM4 in that no prior PI exposure and patients with prior immuno- modulatory drug exposure, notable PFS benefits since patients received maintenance after thalidomide- (48%) or randomization (based on HRs) were seen with ixazomib lenalidomide-containing (52%) induction10; that is, approxi- versus placebo. Although no PFS benefit was seen in the mately half the patients received continuous lenalidomide small subgroup of patients with conventional high-risk cy- through induction and maintenance. Lenalidomide main- togenetics [t(4;14), t(14;16), del(17p)], ixazomib showed tenance after lenalidomide-based induction also demon- a PFS benefit in the larger subgroup with expanded high-risk strated a PFS benefit, overall and since the start of cytogenetics, incorporating patients with amp1q21 in line maintenance, versus placebo or no maintenance in the with the current IMWG definition of high-risk cytogenetics.26 MM-01512 and GIMEMA RV-MM-PI-20929 trials. In the The benefits of ixazomib maintenance were realized in the FIRST trial of transplantation-ineligible patients with NDMM, context of a well-tolerated safety profile and no adverse continuous lenalidomide-dexamethasone since the start of impact on patients’ QoL or HRU, important considerations in therapy demonstrated improved PFS versus fixed-duration this generally elderly, transplantation-ineligible population; lenalidomide-dexamethasone, further highlighting the similar and consistent findings have been reported from other benefit of maintaining long-term lenalidomide therapy.15 phase III studies of ixazomib-based therapy in different However, no significant OS benefits were reported in these Journal of Clinical Oncology 4035 Downloaded from ascopubs.org by 95.127.176.247 on February 17, 2021 from 095.127.176.247 Copyright © 2021 American Society of Clinical Oncology. All rights reserved. Dimopoulos et al No. of Patients with PFS Events B (of total patients) Median PFS (months) HR (95% CI) Subgroup Ixazomib Placebo Ixazomib Placebo All patients (n = 706) 228 of 425 198 of 281 17.4 9.4 0.659 (0.542 to 0.801) Age at time of random assignment < 75 years (n = 432)* 141 of 261 123 of 171 17.7 9.3 0.615 (0.480 to 0.788) ≥ 75 years (n = 274)* 87 of 164 75 of 110 16.7 10.6 0.738 (0.537 to 1.014) Prior PI exposure Yes (n = 566)* 187 of 342 152 of 224 16.8 11.1 0.743 (0.597 to 0.924) No (n = 140)* 41 of 83 46 of 57 24.1 7.7 0.395 (0.251 to 0.622) Preinduction ISS stage I or II (n = 465)* 144 of 281 128 of 184 17.4 10.6 0.641 (0.503 to 0.816) III (n = 241)* 84 of 144 70 of 97 16.6 7.8 0.695 (0.499 to 0.967) Response to initial therapy CR or VGPR (n= 438)* 116 of 263 112 of 175 25.6 12.9 0.586 (0.449 to 0.765) PR (n= 268)* 112 of 162 86 of 106 10.2 6.5 0.756 (0.566 to 1.010) Age < 65 years (n = 68)† 25 of 37 24 of 31 11.5 8.3 0.569 (0.297 to 1.090) ≥ 65 years and < 75 years (n = 365)† 116 of 224 100 of 141 17.9 9.3 0.632 (0.480 to 0.833) ≥ 75 years (n = 273)† 87 of 164 74 of 109 16.7 10.2 0.742 (0.539 to 1.021) Sex Male (n = 377) 129 of 222 113 of 155 15.3 8.3 0.700 (0.539 to 0.909) Female (n = 329) 99 of 203 85 of 126 20.3 12.5 0.620 (0.457 to 0.842) Race White (n = 557) 178 of 330 167 of 227 16.9 9.2 0.602 (0.483 to 0.751) Asian (n = 102) 31 of 63 23 of 39 20.3 14.8 0.826 (0.458 to 1.491) Other or not reported (n = 27) 9 of 17 5 of 10 22.0 18.7 3.152 (0.356 to 27.875) Region Asia-Pacific (n = 118) 36 of 70 32 of 48 18.7 10.7 0.793 (0.471 to 1.337) Europe/Middle East/Africa (n = 505) 164 of 304 143 of 201 16.9 9.3 0.635 (0.503 to 0.801) Other (n = 83) 28 of 51 23 of 32 17.4 9.2 0.672 (0.337 to 1.343) Frailty status Fit (n = 284) 91 of 172 83 of 112 18.6 8.5 0.530 (0.387 to 0.727) Unfit (n = 245) 80 of 147 67 of 98 17.6 10.6 0.746 (0.526 to 1.058) Frail (n = 170) 54 of 102 47 of 68 15.4 11.1 0.733 (0.481 to 1.117) Prior IMiD exposure Yes (n = 231) 72 of 137 73 of 94 18.9 8.7 0.498 (0.350 to 0.708) No (n = 475) 156 of 288 125 of 187 16.6 10.6 0.734 (0.575 to 0.936) ISS stage at initial diagnosis I (n = 178)† 52 of 112 43 of 66 20.3 14.5 0.741 (0.479 to 1.148) II (n = 279)† 90 of 165 84 of 114 15.7 9.4 0.555 (0.403 to 0.765) III (n = 249)† 86 of 148 71 of 101 17.7 7.9 0.712 (0.510 to 0.993) Revised ISS stage at initial diagnosis I (n = 86) 21 of 54 22 of 32 21.8 8.0 0.531 (0.278 to 1.015) II (n = 347) 121 of 204 107 of 143 15.4 9.3 0.667 (0.508 to 0.876) III (n = 92) 36 of 58 24 of 34 15.3 7.8 0.966 (0.544 to 1.714) Unclassifiable (n = 181) 50 of 109 45 of 72 18.6 14.2 0.644 (0.407 to 1.019) Response at study entry CR (n = 163)† 31 of 98 29 of 65 40.5 26.7 0.760 (0.434 to 1.332) VGPR (n = 306)† 97 of 175 102 of 131 17.6 8.7 0.550 (0.410 to 0.737) PR (n = 194)† 82 of 121 60 of 73 11.1 7.4 0.702 (0.491 to 1.004) Cytogenetic risk‡ High risk (n = 122) 51 of 74 36 of 48 10.1 9.6 1.011 (0.631 to 1.621) Standard risk (n = 465) 142 of 275 139 of 190 17.9 9.2 0.617 (0.484 to 0.787) Unclassifiable (n = 119) 35 of 76 23 of 43 22.0 14.3 0.735 (0.401 to 1.347) Cytogenetic risk¶ Expanded high risk (n = 241) 101 of 150 72 of 91 10.8 8.3 0.765 (0.550 to 1.063) Standard risk (n = 256) 70 of 148 77 of 108 18.7 9.3 0.550 (0.388 to 0.780) Unclassifiable (n = 209) 57 of 127 49 of 82 26.7 14.2 0.645 (0.424 to 0.983) Reason for transplantation ineligibility Age (n = 617) 195 of 373 170 of 244 17.6 9.9 0.651 (0.526 to 0.805) Other (n = 70) 28 of 43 20 of 27 14.8 9.3 0.783 (0.413 to 1.484) 0.125 0.25 0.50 1.00 2.00 4.00 8.00 Ixazomib Better Placebo Better FIG 2. (Continued). 4036 © 2020 by American Society of Clinical Oncology Volume 38, Issue 34 Downloaded from ascopubs.org by 95.127.176.247 on February 17, 2021 from 095.127.176.247 Copyright © 2021 American Society of Clinical Oncology. All rights reserved. Ixazomib Maintenance in Patients With Multiple Myeloma Not Undergoing Stem Cell Transplantation TABLE 2. PFS in Patient Subgroups Prespecified for Testing for Statistical Significance, Time to Progression, and Response Improvements Seen With Ixazomib Versus Placebo as Postinduction Maintenance Therapy in the Intention-to-Treat Population Ixazomib Placebo Hazard Ratio Endpoint (n 5 425) (n 5 281) (95% CI) P Median PFS in prespecified subgroups, monthsa,b Patients with a CR or VGPR with initial therapy (n 5 263 v n 5 175) 25.6 12.9 0.586 (0.449 to 0.765) , .001 Patients with preinduction ISS stage III disease (n 5 144 v n 5 97) 16.6 7.8 0.695 (0.499 to 0.967) .030 Patients aged $ 75 years (n 5 164 v n 5 110) 16.7 10.6 0.738 (0.537 to 1.014) .060 Median total PFS landmarked from start of induction, monthsb 26.3 20.3 0.650 (0.534 to 0.791) , .001 Median time to progression, monthsb 17.8 9.6 0.655 (0.537 to 0.799) , .001 Response improvements during maintenance VGPR/PR patients with deepening response during treatment, No. (%) 62 (14.6) 23 (8.2) — .004c VGPR patients converting to CR during study, No. (%) 41 (9.6) 16 (5.7) — — PR patients converting to VGPR or better during study, No. (%) 21 (4.9) 7 (2.5) — — Abbreviations: CR, complete response; ISS, International Staging System; PFS, progression-free survival; PR, partial response; VGPR, very good partial response. a Subgroup testing for PFS was conducted using an alpha of .01 and the Hochberg procedure for multiplicity correction. There was a significant difference with ixazomib versus placebo in patients who had CR or VGPR with initial therapy, and there were benefits in patients with ISS stage III disease and in patients aged $ 75 years, although these did not meet the significance test. b Kaplan-Meier methodology was used to estimate time-to-event distributions, with stratified log-rank tests and Cox models used for interarm comparisons of time-to-event endpoints. c Per the Cochran-Mantel-Haenszel test stratified by response at study entry (PR v VGPR). four studies.10,12,15,29 Similarly, bortezomib-based mainte- treatment of the nontransplantation population, particularly nance after bortezomib-based induction has contributed for elderly patients, and this unique approach may be of to notable overall outcomes in transplantation-ineligible value when considering tailoring treatment to specific patients in the GEM05MAS65,30 GIMEMA-MM-03-05,31 patients. Given the disease heterogeneity of MM, physi- and UPFRONT studies32; however, the specific impact of cians require options that enable them to amend and in- bortezomib-based maintenance or PI-based maintenance dividualize first-line therapy. Prolongation of PFS with more broadly has not been determined in a randomized, ixazomib regardless of the standard-of-care induction placebo-controlled phase III trial. therapy is of potential value as an additional treatment Patients in TOURMALINE-MM4 received induction therapy option, along with continuous therapy approaches15,16 with with a PI-containing and/or immunomodulatory drug– lenalidomide12,29,33,34 or daratumumab8 after lenalidomide- containing regimen at the discretion of their treating phy- based or daratumumab-based induction. sicians. No patients received prior ixazomib, although An alternative approach to long-term PI-based therapy is 82.6% received PI-based induction, resulting in continu- to use ixazomib in a continuous manner similar to that ous PI-based therapy and a median total PFS of approxi- used with lenalidomide12,29,33,34 or daratumumab.8 A mately 26 months. Evaluation of this overall median in the recent analysis of four phase II studies of ixazomib main- context of other data in transplantation-ineligible patients tenance after ixazomib-based induction demonstrated with NDMM is confounded by the immortal time bias aris- the feasibility and activity of this approach. 35 The ing from TOURMALINE-MM4 requiring patients to have phase III, placebo-controlled TOURMALINE-MM2 trial in achieved greater than or equal to PR at enrollment after transplantation-ineligible patients with NDMM compared 6-12 months of standard-of-care induction therapy. Com- ixazomib-lenalidomide-dexamethasone versus placebo- parisons among studies are also confounded by various lenalidomide-dexamethasone for 18 cycles, followed by patient- and disease-related factors, and should be avoided. reduced-dose ixazomib-lenalidomide versus placebo- To our knowledge, TOURMALINE-MM4 is the first ran- lenalidomide from cycle 19 onward. At the time of publi- domized phase III trial to specifically investigate an cation, a PFS benefit with ixazomib-based therapy, with induction-agnostic maintenance approach—randomly a lengthy median, has been reported36 and the publication assigning patients to ixazomib versus placebo regardless of of the full study results is awaited. Transplantation-ineligible the standard-of-care induction therapy received—in patients with NDMM are highly heterogeneous—one transplantation-ineligible NDMM. The feasibility of main- treatment approach does not fit all. An induction-agnostic taining long-term PI-based therapy and convenience of oral maintenance or continuous therapy option may be of value administration with ixazomib are valuable attributes for for optimizing therapy in individual patients. Journal of Clinical Oncology 4037 Downloaded from ascopubs.org by 95.127.176.247 on February 17, 2021 from 095.127.176.247 Copyright © 2021 American Society of Clinical Oncology. All rights reserved. Dimopoulos et al TABLE 3. Treatment Exposure and Overall Safety Profile in the Safety Population Variable Ixazomib (n 5 426)a Placebo (n 5 276)a Treatment cycles, median No. (range) 13 (1-26) 12 (1-26) Dose escalated to 4 mg at cycle $ 5 301 (70.7) 216 (78.3) Median duration of treatment at a dose/placebo equivalent of 4 mg, months (range) 6.0 (0-21) 7.8 (0-21) Completed protocol-specified 26 cycles 68 (16.0) 28 (10.1) b Ongoing on treatment 83 (19.5) 43 (15.3) Mean (SD) relative dose intensity, %c 90.4 (12.63) 96.6 (7.63) Mean (SD) relative dose intensity in patients escalated to 4 mg at cycle 5, %c 93.7 (8.36) 98.6 (3.99) Any TEAE 389 (91.3) 226 (81.9) Any drug-related TEAE 284 (66.7) 111 (40.2) Any grade $ 3 TEAE 156 (36.6) 64 (23.2) Any drug-related grade $ 3 TEAE 76 (17.8) 12 (4.3) Any serious TEAE 94 (22.1) 46 (16.7) Any drug-related serious TEAE 22 (5.2) 3 (1.1) TEAE resulting in discontinuation of the study drug 55 (12.9) 22 (8.0) TEAE resulting in dose reduction of the study drug 131 (30.8) 14 (5.1) d Death during the treatment period 11 (2.6) 6 (2.2) NOTE. Data are No. (%) unless otherwise indicated. Abbreviation: SD, standard deviation; TEAE, treatment-emergent adverse event. a Two patients in the ixazomib group and two patients in the placebo group never received the study drug and were excluded from the safety population. Three patients assigned to the placebo group erroneously received a single dose of ixazomib and were therefore analyzed as part of the ixazomib group in the safety population. b Percentages determined in the intention-to-treat-population (n 5 425; n 5 281) instead of the safety population. c Relative dose intensity is defined as 100 3 (total amount of dose taken) / (total prescribed dose of treated cycles). Total prescribed dose of treated cycles is calculated as: dose prescribed (3 mg, cycles 1-4, 3 mg or 4 mg, cycle 5 onward) 3 prescribed doses per cycle 3 number of treated cycles (calculated separately for cycles 1-4 and cycle 5 onward in patients who escalated to 4 mg at cycle 5 onward). d Death during the treatment period was recorded through 30 days after receiving the last dose of the study drug or placebo. TOURMALINE-MM4 demonstrated the tolerability of ixa- safety profile of ixazomib maintenance in TOURMALINE- zomib maintenance in this elderly population of MM4 was reflected in similar HRU data between arms and transplantation-ineligible patients; 70.7% of patients tol- in patient-reported QoL, which was maintained since study erated the 3-mg dose of ixazomib sufficiently well to es- entry in both arms and was generally similar throughout the calate to 4 mg. Overall rates of TEAEs were similar between treatment period, indicating that active treatment with groups, and TEAEs were mostly grade 1-2 severity. Rates of ixazomib did not have a negative impact on patient- serious TEAEs and discontinuations because of TEAEs reported QoL versus placebo in this double-blind trial. appeared slightly higher with ixazomib versus placebo, In TOURMALINE-MM4, treatment duration was fixed at whereas rates of on-study death and new primary malig- 2 years, based on the duration of bortezomib-based main- nancies appeared similar. Common TEAEs that were more tenance in prior phase III trials.31,37 At the time of trial design, frequent with ixazomib included GI toxicities, rash, and PI-based treat-to-progression approaches had not been peripheral neuropathy; however, rates of grade 3 events studied in a phase III trial, and, to date, the optimal duration were low in both groups. No new safety signals were seen, of PI-based maintenance remains to be determined. Longer- reflecting the findings of TOURMALINE-MM3.20 In the term therapy may have resulted in improved outcomes in Myeloma XI trial of lenalidomide as maintenance post- some patients in TOURMALINE-MM4; however, because transplantation or postinduction, with a median duration median PFS was less than 24 months, the median would be of therapy of eighteen 28-day cycles, 28% of patients who unlikely to be affected. With the favorable tolerability of had discontinued lenalidomide did so because of AEs.10 ixazomib, it was felt that this treatment duration could be Furthermore, lenalidomide appeared to be associated with achieved with minimal discontinuations because of toxicity higher rates of dose modifications (69%) and serious AEs and a reduced risk of developing resistant disease. Never- (45%) 10 than seen in TOURMALINE-MM4 (dose re- theless, because median treatment duration was 13 cycles ductions, 30.8%; serious TEAEs, 22.1%) or TOURMA- and 16.0% of patients completed protocol-specified therapy, LINE-MM3 (19% and 27%, respectively),20 and an treat-to-progression therapy is unlikely to have resulted in elevated risk of new primary malignancies.10 The tolerable prolonged treatment except in a few patients. 4038 © 2020 by American Society of Clinical Oncology Volume 38, Issue 34 Downloaded from ascopubs.org by 95.127.176.247 on February 17, 2021 from 095.127.176.247 Copyright © 2021 American Society of Clinical Oncology. All rights reserved. Ixazomib Maintenance in Patients With Multiple Myeloma Not Undergoing Stem Cell Transplantation TABLE 4. Common TEAEs in the Safety Population ($ 10% in either group or rate difference of $ 5% between ixazomib and placebo groups) Plus Other TEAEs of Clinical Interest Ixazomib Group (n 5 426) Placebo Group (n 5 276) Adverse Event Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4 Common hematologic TEAEs of any cause Thrombocytopeniaa 20 (4.7) 9 (2.1) 0 (0.0) 1 (0.4) 0 (0.0) 0 (0.0) a Neutropenia 10 (2.3) 8 (1.9) 1 (0.2) 9 (3.3) 4 (1.4) 0 (0.0) Common nonhematologic TEAEs of any cause GI disorders (MedDRA SOC) 222 (52.1) 22 (5.2) 0 (0.0) 93 (33.7) 7 (2.5) 0 (0.0) Nausea 114 (26.8) 2 (0.5) 0 (0.0) 22 (8.0) 0 (0.0) 0 (0.0) Vomiting 103 (24.2) 7 (1.6) 0 (0.0) 12 (4.3) 2 (0.7) 0 (0.0) Diarrhea 99 (23.2) 8 (1.9) 0 (0.0) 34 (12.3) 2 (0.7) 0 (0.0) Infections and infestations (MedDRA SOC)b 206 (48.4) 28 (6.6) 0 (0.0) 104 (37.7) 12 (4.3) 0 (0.0) Upper respiratory tract infection 67 (15.7) 2 (0.5) 0 (0.0) 30 (10.9) 1 (0.4) 0 (0.0) Rasha 109 (25.6) 12 (2.8) 0 (0.0) 29 (10.5) 0 (0.0) 0 (0.0) a Peripheral neuropathy 83 (19.5) 7 (1.6) 0 (0.0) 30 (10.9) 0 (0.0) 0 (0.0) Back pain 61 (14.3) 1 (0.2) 0 (0.0) 31 (11.2) 1 (0.4) 0 (0.0) Arthralgia 49 (11.5) 2 (0.5) 0 (0.0) 20 (7.2) 2 (0.7) 0 (0.0) Pyrexia 48 (11.3) 1 (0.2) 0 (0.0) 14 (5.1) 0 (0.0) 1 (0.4) Fatigue 46 (10.8) 6 (1.4) 0 (0.0) 28 (10.1) 1 (0.4) 0 (0.0) Other TEAEs of clinical interest Cardiac arrhythmiasa,c 18 (4.2) 6 (1.4) 0 (0.0) 13 (4.7) 2 (0.7) 0 (0.0) a,d Heart failure 5 (1.2) 2 (0.5) 0 (0.0) 4 (1.4) 1 (0.4) 1 (0.4) Hypotensiona 10 (2.3) 0 (0.0) 0 (0.0) 3 (1.1) 0 (0.0) 0 (0.0) Liver impairmenta 19 (4.5) 6 (1.4) 0 (0.0) 7 (2.5) 3 (1.1) 0 (0.0) Myocardial infarctiona,e 1 (0.2) 0 (0.0) 1 (0.2) 4 (1.4) 1 (0.4) 0 (0.0) a,f Renal impairment 16 (3.8) 4 (0.9) 4 (0.9) 5 (1.8) 0 (0.0) 0 (0.0) Herpes zoster 13 (3.1) 1 (0.2) 0 (0.0) 2 (0.7) 0 (0.0) 0 (0.0) In patients receiving antiviral prophylaxis 1/274 (0.4) 0 (0.0) 0 (0.0) 0/167 (0.0) 0 (0.0) 0 (0.0) In patients not receiving prophylaxis 12/152 (7.9) 1/152 (0.7) 0 (0.0) 2/109 (1.8) 0 (0.0) 0 (0.0) New primary malignant tumor 22 (5.2) — 17 (6.2) — NOTE. Data are No. (%). Abbreviations: MedDRA, Medical Dictionary for Regulatory Activities; SOC, system organ class; TEAEs, treatment-emergent adverse events. a Data were based on a standardized MedDRA query that incorporated pooled preferred terms or multiple preferred terms. Preferred terms included within each standardized MedDRA query are summarized in the Data Supplement. b Seven patients (1.6%) in the ixazomib group and one patient (0.4%) in the placebo group had grade 5 infections and infestations events, including septic shock (n 5 6), sepsis (n 5 2), and viral pneumonia (n 5 1) in the ixazomib group and septic shock (n 5 1) in the placebo group. c One patient (0.2%) in the ixazomib group had a grade 5 event of cardiac arrest, and one (0.4%) in the placebo group had a grade 5 event of sudden death. d One patient (0.2%) in the ixazomib group had grade 5 acute pulmonary edema. e One patient (0.4%) in the placebo group had grade 5 myocardial infarction. f One patient (0.2%) in the ixazomib group had grade 5 acute kidney injury. In conclusion, to our knowledge, ixazomib is the first elderly patients, those with preinduction ISS stage III disease, induction-agnostic maintenance option investigated for and patients achieving CR or VGPR postinduction. Further- transplantation-ineligible patients with NDMM. These re- more, ixazomib may provide a valuable maintenance option in sults indicate that ixazomib is well tolerated and provides combination with other agents, such as immunomodulatory a PFS benefit in this setting, thereby representing a valu- drugs and monoclonal antibodies. TOURMALINE-MM4 able treatment option for patients. Subgroup analyses continues in a double-blind fashion for long-term evaluation suggest PFS benefit across this population, including in of PFS2 and OS. Journal of Clinical Oncology 4039 Downloaded from ascopubs.org by 95.127.176.247 on February 17, 2021 from 095.127.176.247 Copyright © 2021 American Society of Clinical Oncology. All rights reserved. Dimopoulos et al AFFILIATIONS presented at the virtual 25th Annual Congress of the European 1 Hematology and Medical Oncology, Department of Clinical Hematology Association, The Hague, Netherlands, June 11-21, 2020. Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece SUPPORT 2 First Department of Medicine, Department of Hematology, First Faculty Sponsored by Millennium Pharmaceuticals, Inc., a wholly owned of Medicine, Charles University and General Hospital in Prague, Prague, subsidiary of Takeda Pharmaceutical Company Limited. Czech Republic 3 Department of Hematology, University of Melbourne, St Vincent’s Hospital, Melbourne, Victoria, Australia CLINICAL TRIAL INFORMATION 4 Institut d’Investigació contra la Leucèmia Josep Carreras and Institut NCT02312258 Català d’Oncologia, Hospital Germans Trias i Pujol, Badalona, Spain 5 Department of Hemato-oncology, University Hospital Ostrava, University AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF of Ostrava, and Faculty of Medicine, Ostrava, Czech Republic INTEREST 6 Hematology, Leicester Royal Infirmary/University Hospitals of Leicester Disclosures provided by the authors are available with this article at DOI NHS Trust, Leicester, United Kingdom 7 https://doi.org/10.1200/JCO.20.02060 Department of Hematology, Ankara University, Ankara, Turkey 8 Division of Hematology, University of Torino, Azienda Ospedaliero- Universitaria Città della Salute e della Scienza di Torino, Torino, Italy AUTHOR CONTRIBUTIONS 9 Department of Hematology, Theagenion Cancer Hospital, Thessaloniki, Conception and design: Meletios A. Dimopoulos, Wee-Joo Chng, Xavier Greece Leleu, Gareth Morgan, Richard Labotka, Antonio Palumbo, Sagar Lonial 10 Department of Hematology-Oncology, National University Cancer Provision of study materials or patients: Meletios A. Dimopoulos, Albert Institute, National University Health System, and Yong Loo Lin School of Oriol, Mamta Garg, Meral Beksac, Sara Bringhen, Wee-Joo Chng, Xavier Medicine and Cancer Science Institute of Singapore, National University Leleu, Marı́a-Victoria Mateos, Sagar Lonial of Singapore, Singapore Collection and assembly of data: Meletios A. Dimopoulos, Ivan Špička, 11 Pôle Régional de Cancérologie, Department of Haematology, Centre Hang Quach, Albert Oriol, Roman Hájek, Mamta Garg, Meral Beksac, Hospitalier Universitaire La Milétrie-Poitiers, Poitiers, France Sara Bringhen, Eirini Katodritou, Wee-Joo Chng, Xavier Leleu, Shinsuke 12 Department of Hematology and Oncology, Nagoya City University Iida, Marı́a-Victoria Mateos, Alexander Vorog Graduate School of Medical Sciences, Nagoya, Japan Data analysis and interpretation: All authors 13 Hematology, Hospital Universitario de Salamanca, University Hospital Manuscript writing: All authors of Salamanca, Centro de Investigación del Cáncer, Instituto de Biologı́a Final approval of manuscript: All authors Molecular y Celular del Cáncer, (Universitario de Salamanca Consejo Accountable for all aspects of the work: All authors Superior de Investigaciones Cientı́ficas), Salamanca, Spain 14 Perlmutter Cancer Center, NYU Langone Health, New York, NY ACKNOWLEDGMENT 15 Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of This study was sponsored by Millennium Pharmaceuticals, Inc., a wholly Takeda Pharmaceutical Company Limited, Cambridge, MA 16 owned subsidiary of Takeda Pharmaceutical Company Limited. The trial Department of Hematology and Medical Oncology, Winship Cancer was designed by the authors in collaboration with the sponsor. Data were Institute of Emory University, Atlanta, GA gathered by the investigators and sponsor, and analyzed by the sponsor. The sponsor funded professional medical writing support to prepare the CORRESPONDING AUTHOR manuscript. We thank the patients and their families, as well as the Meletios A. Dimopoulos, MD, Hematology and Medical Oncology, physicians, nurses, study coordinators, and research staff for Department of Clinical Therapeutics, National and Kapodistrian participation in the trial; Dasha Cherepanov, PhD, and Lauren Cain, PhD, University of Athens, School of Medicine, Alexandra General Hospital, 80 of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Vasilisis Sophias, 11528, Athens, Greece: e-mail: mdimop@med.uoa.gr. Takeda Pharmaceutical Company Limited, for their contributions to health-related quality of life and health care resource use analyses and interpretations; Renda Ferrari, PhD, of Millennium Pharmaceuticals, PRIOR PRESENTATION Inc., for editorial assistance; and Steve Hill, PhD, of FireKite, an Ashfield Poster presented at the ASCO20 Virtual Annual Meeting of the American company, part of UDG Healthcare, for professional medical writing Society of Clinical Oncology, Chicago, IL, May 29-31, 2020; paper assistance, which was funded by Millennium Pharmaceuticals, Inc. REFERENCES 1. Palumbo A, Gay F, Cavallo F, et al: Continuous therapy versus fixed duration of therapy in patients with newly diagnosed multiple myeloma. J Clin Oncol 33: 3459-3466, 2015 2. Ludwig H, Zojer N: Fixed duration vs continuous therapy in multiple myeloma. Hematology (Am Soc Hematol Educ Program) 2017:212-222, 2017 3. 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Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al: Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: Results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol 30:2946-2955, 2012 n n n Journal of Clinical Oncology 4041 Downloaded from ascopubs.org by 95.127.176.247 on February 17, 2021 from 095.127.176.247 Copyright © 2021 American Society of Clinical Oncology. All rights reserved. Dimopoulos et al AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Ixazomib as Postinduction Maintenance for Patients With Newly Diagnosed Multiple Myeloma Not Undergoing Autologous Stem Cell Transplantation: The Phase III TOURMALINE-MM4 Trial The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 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/authors/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Meletios A. Dimopoulos Xavier Leleu Honoraria: Amgen, Celgene, Takeda, Janssen-Cilag, Bristol Myers Squibb Honoraria: Janssen-Cilag, Celgene, Amgen, Novartis, Bristol Myers Squibb, Consulting or Advisory Role: Amgen, Janssen-Cilag, Takeda, Celgene, Bristol Takeda, Sanofi, AbbVie, Merck, Roche, Karyopharm Therapeutics, Carsgen Myers Squibb Therapeutics, Oncopeptides, GSK Consulting or Advisory Role: Janssen-Cilag, Celgene, Amgen, Takeda, Bristol Ivan Špička Myers Squibb, Novartis, Merck, Gilead Sciences, AbbVie, Roche, Karyopharm Honoraria: Celgene, Amgen, Janssen-Cilag, Takeda, Novartis Therapeutics, Oncopeptides, Carsgen Therapeutics, GSK Consulting or Advisory Role: Celgene, Amgen, Janssen-Cilag, Takeda, Novartis, Travel, Accommodations, Expenses: Takeda Sanofi Speakers’ Bureau: Celgene, Amgen, Janssen-Cilag, Takeda, BMS, Novartis, Shinsuke Iida Sanofi Honoraria: Takeda, Celgene, Janssen, Daiichi Sankyo, Ono Pharmaceutical, Travel, Accommodations, Expenses: Celgene, Amgen, Janssen-Cilag, BMS Sanofi, Ono Pharmaceutical, Takeda, Janssen, GlaxoSmithKline, AbbVie Research Funding: Takeda (Inst), Chugai Pharma (Inst), Kyowa Hakko Kirin Hang Quach (Inst), Ono Pharmaceutical (Inst), Sanofi (Inst), Bristol Myers Squibb Japan Consulting or Advisory Role: GlaxoSmithKline, Celgene, Karyopharm (Inst), Janssen (Inst), AbbVie (Inst) Therapeutics, Janssen-Cilag, CSL Behring, Amgen, Sanofi Research Funding: Celgene, Amgen, Karopharm, GlaxoSmithKline, Sanofi Maria-Victoria Mateos Honoraria: Janssen-Cilag, Celgene, Amgen, Takeda, GSK, AbbVie/Genentech, Albert Oriol Adaptive Consulting or Advisory Role: Celgene, Janssen, Amgen, Sanofi, GSK Consulting or Advisory Role: Takeda, Janssen-Cilag, Celgene, Amgen, AbbVie, Speakers’ Bureau: Amgen, Celgene GlaxoSmithKline, Pharmamar-Zeltia Roman Hájek Gareth Morgan Consulting or Advisory Role: Takeda, Amgen, Celgene, AbbVie, BMS, Honoraria: BMS, Janssen, Genentech, Sanofi, Karyopharm, Takeda PharmaMar, Janssen-Cilag, Novartis Consulting or Advisory Role: Takeda, GSK Speakers’ Bureau: Takeda, Amgen Travel, Accommodations, Expenses: BMS, Janssen Research Funding: Novartis (Inst), BMS (Inst), Amgen (Inst), Celgene (Inst), Takeda (Inst) Alexander Vorog Employment: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Mamta Garg Takeda Pharmaceutical Company Limited Travel, Accommodations, Expenses: Takeda Richard Labotka Meral Beksac Employment: Takeda Pharmaceuticals, Millennium Pharmaceuticals, Inc., Consulting or Advisory Role: Celgene (Inst), Janssen-Cilag (Inst), Amgen (Inst), a wholly owned subsidiary of Takeda Pharmaceutical Company Limited Takeda (Inst), Sanofi Pasteur (Inst), Oncopeptides Speakers’ Bureau: Amgen (Inst), Celgene (Inst), Janssen-Cilag (Inst), Sanofi Bingxia Wang Pasteur (Inst) Employment: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited Sara Bringhen Honoraria: Celgene, Amgen, Bristol Myers Squibb, Janssen-Cilag Antonio Palumbo Consulting or Advisory Role: Celgene, Janssen-Cilag, Takeda, Karyopharm, Employment: Takeda, Millennium Pharmaceuticals, Inc., a wholly owned Amgen subsidiary of Takeda Pharmaceutical Company Limited Travel, Accommodations, Expenses: Amgen, Celgene, Janssen-Cilag Stock and Other Ownership Interests: Takeda Honoraria: Takeda Eirini Katodritou Consulting or Advisory Role: Takeda Honoraria: Takeda, Janseen-Cilag, Amgen, Genesis-Pharma Research Funding: Takeda (Inst) Consulting or Advisory Role: Amgen, Janseen-Cilag Travel, Accommodations, Expenses: Takeda Research Funding: Takeda, Amgen, Janseen-Cilag, Genesis-Pharma Travel, Accommodations, Expenses: Genesis-Pharma, Takeda Sagar Lonial Stock and Other Ownership Interests: TG Therapeutics Wee-Joo Chng Consulting or Advisory Role: Celgene, Bristol Myers Squibb, Janssen Oncology, Honoraria: Johnson and Johnson, Amgen, Celgene, Takeda, AbbVie Novartis, GlaxoSmithKline, Amgen, AbbVie, Takeda, Merck, Juno Therapeutics Research Funding: Janssen (Inst), Celgene (Inst), Amgen (Inst) Speakers’ Bureau: Sanofi Research Funding: Celgene, Bristol Myers Squibb, Takeda Other Relationship: TG Therapeutics No other potential conflicts of interest were reported. © 2020 by American Society of Clinical Oncology Volume 38, Issue 34 Downloaded from ascopubs.org by 95.127.176.247 on February 17, 2021 from 095.127.176.247 Copyright © 2021 American Society of Clinical Oncology. All rights reserved.