Reporting of Postprotocol Therapies and Attrition in Multiple Myeloma Randomized Clinical Trials: A Systematic Review | Hematology | JAMA Network Open | JAMA Network
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Figure.  Flow Diagram
Flow Diagram
Table 1.  Characteristics of 103 Included Studies
Characteristics of 103 Included Studies
Table 2.  Pivotal Frontline Trials and Their Reporting/Description of Postprotocol Treatments
Pivotal Frontline Trials and Their Reporting/Description of Postprotocol Treatments
Table 3.  Pivotal Relapsed/Refractory Trials and Their Reporting and Description of Postprotocol Treatments
Pivotal Relapsed/Refractory Trials and Their Reporting and Description of Postprotocol Treatments
1.
Rajkumar  SV.  Multiple myeloma: 2020 update on diagnosis, risk-stratification and management.   Am J Hematol. 2020;95(5):548-567. doi:10.1002/ajh.25791 PubMedGoogle ScholarCrossref
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Siegel  DS, Dimopoulos  MA, Ludwig  H,  et al.  Improvement in overall survival with carfilzomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma.   J Clin Oncol. 2018;36(8):728-734. doi:10.1200/JCO.2017.76.5032 PubMedGoogle ScholarCrossref
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Durie  BGM, Hoering  A, Sexton  R,  et al.  Longer term follow-up of the randomized phase III trial SWOG S0777: bortezomib, lenalidomide and dexamethasone vs. lenalidomide and dexamethasone in patients (Pts) with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant (ASCT).   Blood Cancer J. 2020;10(5):53. doi:10.1038/s41408-020-0311-8 PubMedGoogle ScholarCrossref
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Gyawali  B, Prasad  V.  Combining drugs and extending treatment—a PFS end point is not sufficient.   Nat Rev Clin Oncol. 2017;14(9):521-522. doi:10.1038/nrclinonc.2017.72 PubMedGoogle ScholarCrossref
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Sledge  GW, Neuberg  D, Bernardo  P,  et al.  Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193).   J Clin Oncol. 2003;21(4):588-592. doi:10.1200/JCO.2003.08.013 PubMedGoogle ScholarCrossref
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Liberati  A, Altman  DG, Tetzlaff  J,  et al.  The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.   J Clin Epidemiol. 2009;62(10):e1-e34. doi:10.1016/j.jclinepi.2009.06.006 PubMedGoogle ScholarCrossref
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Kumar  S, Facon  T, Usmani  S,  et al .  Updated analysis of daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM): the phase 3 MAIA Study.   Blood. 2020;136(suppl 1):24-26. doi:10.1182/blood-2020-134847Google ScholarCrossref
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Mateos  MV, Cavo  M, Blade  J,  et al.  Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial.   Lancet. 2020;395(10218):132-141. doi:10.1016/S0140-6736(19)32956-3 PubMedGoogle ScholarCrossref
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San Miguel  JF, Schlag  R, Khuageva  NK,  et al.  Continued overall survival benefit after 5 years' follow-up with bortezomib-melphalan-prednisone (VMP) versus melphalan-prednisone (MP) in patients with previously untreated multiple myeloma, and no increased risk of second primary malignancies: final results of the phase 3 VISTA trial.   Blood. 2011;118(21):476. doi:10.1182/blood.V118.21.476.476Google ScholarCrossref
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Palumbo  A, Hajek  R, Delforge  M,  et al; MM-015 Investigators.  Continuous lenalidomide treatment for newly diagnosed multiple myeloma.   N Engl J Med. 2012;366(19):1759-1769. doi:10.1056/NEJMoa1112704 PubMedGoogle ScholarCrossref
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Rajkumar  SV, Jacobus  S, Callander  NS,  et al; Eastern Cooperative Oncology Group.  Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial.   Lancet Oncol. 2010;11(1):29-37. doi:10.1016/S1470-2045(09)70284-0 PubMedGoogle ScholarCrossref
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Facon  T, Dimopoulos  MA, Dispenzieri  A,  et al.  Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma.   Blood. 2018;131(3):301-310. doi:10.1182/blood-2017-07-795047 PubMedGoogle ScholarCrossref
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Weisel  M, Sonneveld  P, Mateos  MV  et al.  Efficacy and safety of daratumumab, bortezomib, and dexamethasone (D-Vd) versus bortezomib and dexamethasone (Vd) in first relapse patients (pts) with multiple myeloma (MM): four-year update of CASTOR.   Blood. 2019;134(suppl 1):3192. doi:10.1182/blood-2019-123527 Google ScholarCrossref
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Spencer  A, Lentzsch  S, Weisel  K,  et al.  Daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of CASTOR.   Haematologica. 2018;103(12):2079-2087. doi:10.3324/haematol.2018.194118 PubMedGoogle ScholarCrossref
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Weisel  K, Spencer  A, Lentzsch  S,  et al.  Daratumumab, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma: subgroup analysis of CASTOR based on cytogenetic risk.   J Hematol Oncol. 2020;13(1):115. doi:10.1186/s13045-020-00948-5 PubMedGoogle ScholarCrossref
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Bahlis  NJ, Dimopoulos  MA, White  DJ,  et al.  Daratumumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended follow-up of POLLUX, a randomized, open-label, phase 3 study.   Leukemia. 2020;34(7):1875-1884. doi:10.1038/s41375-020-0711-6 PubMedGoogle ScholarCrossref
19.
Dimopoulos  MA, Goldschmidt  H, Niesvizky  R,  et al.  Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial.   Lancet Oncol. 2017;18(10):1327-1337. doi:10.1016/S1470-2045(17)30578-8 PubMedGoogle ScholarCrossref
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 Prepare and plan for financial constraints on clinical trials.   J Oncol Pract. 2007;3(1):37-38. doi:10.1200/JOP.0714701 PubMedGoogle ScholarCrossref
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Joseph  NS, Kaufman  JL, Dhodapkar  MV,  et al.  Long-term follow-up results of lenalidomide, bortezomib, and dexamethasone induction therapy and risk-adapted maintenance approach in newly diagnosed multiple myeloma.   J Clin Oncol. 2020;38(17):1928-1937. doi:10.1200/JCO.19.02515 PubMedGoogle ScholarCrossref
22.
Fonseca  R, Abouzaid  S, Bonafede  M,  et al.  Trends in overall survival and costs of multiple myeloma, 2000-2014.   Leukemia. 2017;31(9):1915-1921. doi:10.1038/leu.2016.380 PubMedGoogle ScholarCrossref
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Thorsteinsdottir  S, Dickman  PW, Landgren  O,  et al.  Dramatically improved survival in multiple myeloma patients in the recent decade: results from a Swedish population-based study.   Haematologica. 2018;103(9):e412-e415. doi:10.3324/haematol.2017.183475 PubMedGoogle ScholarCrossref
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Dimopoulos  M, Weisel  K, Moreau  P,  et al.  Pomalidomide, bortezomib, and dexamethasone for multiple myeloma previously treated with lenalidomide (OPTIMISMM): outcomes by prior treatment at first relapse.   Leukemia. 2020. doi:10.1038/s41375-020-01021-3PubMedGoogle Scholar
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Voorhees  PM, Kaufman  JL, Laubach  J,  et al.  Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial.   Blood. 2020;136(8):936-945. doi:10.1182/blood.2020005288 PubMedGoogle ScholarCrossref
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Daratumumab  VELCADE, (bortezomib), lenalidomide and dexamethasone compared to VELCADE, lenalidomide and dexamethasone in subjects with previously untreated multiple myeloma. ClinicalTrials.gov Identifier: NCT03710603. Updated July 21, 2020. Accessed December 15, 2020. https://www.clinicaltrials.gov/ct2/show/NCT03710603
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Attal  M, Lauwers-Cances  V, Hulin  C,  et al; IFM 2009 Study.  Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma.   N Engl J Med. 2017;376(14):1311-1320. doi:10.1056/NEJMoa1611750 PubMedGoogle ScholarCrossref
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Tacchetti  P, Pantani  L, Patriarca  F,  et al; GIMEMA (Gruppo Italiano Malattie Ematologiche dell’Adulto Italian Myeloma Network).  Bortezomib, thalidomide, and dexamethasone followed by double autologous haematopoietic stem-cell transplantation for newly diagnosed multiple myeloma (GIMEMA-MMY-3006): long-term follow-up analysis of a randomised phase 3, open-label study.   Lancet Haematol. 2020;7(12):e861-e873. doi:10.1016/S2352-3026(20)30323-9 PubMedGoogle ScholarCrossref
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Fonseca  R, Usmani  SZ, Mehra  M,  et al.  Frontline treatment patterns and attrition rates by subsequent lines of therapy in patients with newly diagnosed multiple myeloma.   BMC Cancer. 2020;20(1):1087. doi:10.1186/s12885-020-07503-y PubMedGoogle ScholarCrossref
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Richardson  PG, San Miguel  JF, Moreau  P,  et al.  Interpreting clinical trial data in multiple myeloma: translating findings to the real-world setting.   Blood Cancer J. 2018;8(11):109. doi:10.1038/s41408-018-0141-0 PubMedGoogle ScholarCrossref
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Lavori  PW, Dawson  R.  Introduction to dynamic treatment strategies and sequential multiple assignment randomization.   Clin Trials. 2014;11(4):393-399. doi:10.1177/1740774514527651 PubMedGoogle ScholarCrossref
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    Original Investigation
    Oncology
    April 28, 2021

    Reporting of Postprotocol Therapies and Attrition in Multiple Myeloma Randomized Clinical Trials: A Systematic Review

    Author Affiliations
    • 1Department of Hematological Malignancies and Cellular Therapeutics, Kansas University Medical Center, Kansas City
    • 2Division of Blood and Marrow Transplantation, University of California, San Diego, La Jolla
    • 3Divisions of Hematology & Medical Oncology, University of California, San Francisco
    JAMA Netw Open. 2021;4(4):e218084. doi:10.1001/jamanetworkopen.2021.8084
    Key Points

    Question  What proportion of multiple myeloma randomized clinical trials report postprotocol therapies, and when reported, how do these therapies compare with existing standard of care?

    Findings  In this systematic review of 103 randomized clinical trials including 47 251 patients, only 43.7% of the trials reported postprotocol therapies. When described, the proportion of patients receiving postprotocol therapies was low, and often not at par with standard of care therapy.

    Meaning  These findings suggest that reporting of postprotocol therapies is poor in multiple myeloma trials, necessitating reporting guidelines on postprotocol therapies for ongoing and future trials.

    Abstract

    Importance  A thorough understanding of the optimal role and sequence of agents for treatment of multiple myeloma (MM) requires knowledge of the use and rate of postprotocol therapies in randomized clinical trials (RCTs).

    Objectives  To examine the proportion of MM RCTs that reported postprotocol therapies and, among those, the percentage of patients who received no further therapy and how treatments differed between the control and intervention arms.

    Evidence Review  The reporting of postprotocol therapies was systematically assessed in published MM RCTs using 3 databases (PubMed, Embase, and Cochrane Registry of Controlled Trials) for MM RCTs from January 1, 2005, to December 30, 2019. All MM RCTs were included, and all other studies, such as editorials, nonrandomized studies, and review articles, were excluded.

    Findings  A total of 103 RCTs were identified (47 251 patients); of these, 45 (43.7%) reported subsequent treatments in that publication or in any subsequent publication. Trials funded by pharmaceutical companies (26 of 47 [55.3%]) were more likely to report subsequent treatments than cooperative group studies (19 of 56 [33.9%]) (χ21,103 = 4.8; P = .03). Differences were found in the treatments received between the intervention and control arms of RCTs. When data were reported, 5150 of 9351 patients (54.9%) in RCTs of newly diagnosed MM and 2197 of 4501 patients (48.8%) in RCTs of relapsed/refractory MM received any subsequent therapy.

    Conclusions and Relevance  Postprotocol therapies in MM RCTs are often not reported and, when they are, many patients receive no further therapy. Reporting guidelines for postprotocol therapies are needed.

    Introduction

    Advances in the treatment of multiple myeloma (MM) have led to improved survival.1 Triplet therapy is recommended at diagnosis and relapse, because multiple randomized clinical trials (RCTs) have demonstrated the superiority of triplet over doublet therapy with respect to efficacy outcomes, such as progression-free survival (PFS) and overall survival (OS).2-4 To our knowledge, there has not been a systematic review of reporting on postprotocol therapies of patients in these trials. An understanding of the rate and quality of postprotocol therapies is necessary to assess whether combined use of multiple agents is superior to the sequential use of these agents in accordance with the best available standard of care before the study.5 Some contend that, in the absence of improvements in OS or quality of life, gains in PFS alone do not justify the use of drugs in combination that were previously used in sequence.6,7

    For these reasons, we sought to systematically assess the reporting of postprotocol therapies in MM RCTs published from 2005 to 2019. We also aimed to determine what fraction of patients received no further therapies in trials in which those data were reported.

    Methods
    Search Strategy

    We performed a search of 3 databases: (MEDLINE/PubMed, Embase, and Cochrane Registry of Controlled Trials). An example search strategy using Embase is highlighted in the eTable in the Supplement. Two of us (G.R.M. and K.K.) independently screened all studies and any conflict was resolved through mutual discussion. This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.8

    Our search strategy was restricted to include RCTs that were published in manuscript or abstract form from January 1, 2005, to December 30, 2019. The search was last updated on April 1, 2020. All other publications, including editorials, case reports, case series, review articles, case-control studies, retrospective/prospective cohort studies, and single-arm studies, were excluded. Furthermore, trials not evaluating therapeutic interventions, such as those focusing solely on supportive care measures, infection mitigation preventions, or different stem cell mobilization strategies, were excluded. The search strategy was not restricted by language. Abstracts from conference proceedings that were captured on these databases via our search strategy, such as those on Embase, were also included.

    Two of us (G.R.M. and K.K.) performed and verified all data extraction. Extracted data were tabulated using Microsoft Excel (Microsoft Corp). We identified the disease phase (relapsed/refractory or frontline) and location of study (enrollment in the US alone vs multinational). The most recent article or abstract with updated data was used to collect data for each study.

    The primary outcomes were the proportion of RCTs that reported postprotocol therapies and, in trials that reported postprotocol therapies, the percentage of patients who received no further therapy.

    For quantitative estimation of attrition and receipt of subsequent therapy, we only included studies that clearly reported the number of patients receiving subsequent therapies in both the control and intervention arm. Studies that only reported on a particular type of therapy or only on one arm were excluded from the quantitative analysis.

    Statistical Analysis

    Analysis with χ2 testing was used to calculate differences in proportions between trials funded by pharmaceutical companies vs cooperative group studies, whenever applicable. Significance testing was 2 sided, and differences at P < .05 were considered significant. Data analysis was performed using SPSS, version 26 (IBM).

    Results

    After excluding duplicate RCTs and trials that did not meet the inclusion criteria, a total of 103 discrete RCTs were identified (47 251 patients) (Figure). Table 1 highlights the characteristics of the included studies.

    We found 45 of the 103 RCTs (43.7%) that reported subsequent treatments in the original article or in any follow-up publication or abstract. Among these 45 trials, the subsequent treatments were reported in the main article in 11 studies (24.4%), in a supplemental appendix in 11 studies (24.4%), and in a subsequent abstract presentation in 23 studies (51.1%).

    Among 47 pharmaceutical company–funded RCTs, postprotocol therapies were reported in 26 (55.3%). Among 56 cooperative group RCTs, postprotocol therapies were reported in 19 (33.9%). This difference was statistically significant (χ21,103 = 4.8; P = .03).

    Attrition Rates

    Among the 45 RCTs that reported subsequent therapies, 27 (60.0%) reported clearly on the number of patients in both the control and intervention arms who subsequently received therapy. Among 7665 patients in the intervention arms of these trials, only 3845 (50.2%) received a subsequent (nonmaintenance) line of therapy. Among 6801 patients in the control arms of these trials, 3793 (55.8%) eventually received a subsequent line of therapy.

    We stratified receipt of subsequent therapy for frontline and relapsed/refractory trials. In RCTs of newly diagnosed MM, subsequent systemic treatment was received by 2472 of 4248 (58.2%) patients enrolled in the control arms and 2668 of 5103 (52.3%) patients in the intervention arms (overall, 5150 of 9351 [54.9%]). In RCTs of relapsed/refractory MM, subsequent systemic treatment was received by 1148 of 2246 (51.1%) patients enrolled in the control arms and 1049 of 2255 (46.5%) patients in the intervention arms (overall, 2197 of 4501 [48.8%]). Consequently, 45.1% of patients in newly diagnosed MM RCTs and 51.2% of patients in the relapsed/refractory RCT setting received no further therapy.

    Among the 27 RCTs that reported clearly on the number of patients receiving subsequent therapies, 13 were funded by pharmaceutical companies (48.1%) and 14 were cooperative group studies (51.9%). Among the 13 pharmaceutical company–funded studies, 4187 of 8375 patients (50.0%) received subsequent therapies, whereas in the 14 cooperative group studies, 3451 of 6091 patients (56.7%) received subsequent therapies (P < .001).

    Translation of a PFS to an OS Benefit

    In 45 RCTs (43.7%) in which subsequent treatment was clearly reported, a PFS benefit was reported in 38 (84.4%) of these trials. Based on the most recent follow-up of patients, this PFS benefit translated to an OS benefit in 17 of RCTs (44.7% of those that reported a PFS advantage) and had not yet resulted or did not result in a benefit in the remaining trials (21 [55.3%]). In 59 RCTs that did not report subsequent treatment, 22 (37.3%) described a PFS and an OS benefit was seen in 5 trials (22.7% of trials that reported a PFS benefit).

    Postprotocol Treatments for Pivotal Trials

    We assessed the description of subsequent treatments for major practice-changing trials over the past 15 years. Table 2 highlights pivotal trials in the frontline setting with respect to their reporting and practices of postprotocol treatments.4,9-14 Receipt of daratumumab post progression was low in the MAIA9 and ALCYONE10 trials. The SWOG 0777 trial, which evaluated combined bortezomib, lenalidomide, and dexamethasone vs combined lenalidomide and dexamethasone, did not report on subsequent treatments in a follow-up publication; hence, it is unknown what proportion of patients randomized to lenalidomide and dexamethasone received bortezomib at progression of MM.4

    Table 3 highlights the reporting and practices of postprotocol treatments in pivotal trials evaluating the relapsed/refractory MM setting.2,3,15-19 In pivotal triplet vs doublet therapy trials, such as ASPIRE (carfilzomib, lenalidomide, and dexamethasone)2 and ELOQUENT-2 (elotuzumab, lenalidomide, and dexamethasone vs lenalidomide and dexamethasone),3 use of carfilzomib and elotuzumab was low in the control arm. Conversely, most patients in the control arm of the CASTOR trial (daratumumab/bortezomib/dexamethasone vs bortezomib/dexamethasone) received daratumumab at progression.15

    Discussion

    Despite treatment advances, most patients with MM relapse. Hence, combinations of treatments are attempted in sequence to reduce tumor burden, improving quality and quantity of life. The clinical question of whether to use the available armamentarium of drugs early in the course or to reserve them for sequential administration is relevant. To understand the value of a combination in improving overall survival, an overall accurate reporting of crossover and postprotocol therapies is required.

    Our systematic review noted that reporting of postprotocol therapies for MM RCTs is low, occurring only in 43.7% of trials. Because subsequent therapies were not reported line by line, we were only able to determine whether patients received any subsequent therapy—not how many lines of therapies they subsequently received. Even for pivotal practice-changing trials, such as SWOG 0777, which established the efficacy of combined bortezomib, lenalidomide, and dexamethasone as frontline treatment for MM, postprotocol treatments were not reported in the follow-up publication.4 The reporting rate for postprotocol therapies was significantly lower in cooperative group studies (33.9%) compared with pharmaceutical company–funded RCTs (55.3%). This difference is likely related to budgetary constraints of cooperative group trials20 and deserves further study across different diseases. Conversely though, when reported, receipt of postprotocol therapies was higher in cooperative group studies than in pharmaceutical studies, a finding that may reflect the settings in which the trial enrolled patients.

    It is undeniable that the new agents available for MM have led to markedly improved survival, as reported both by contemporary clinical trial data and real-world observational data.21-23 It is also true that this improvement in survival is associated both with increased use of combination therapies and availability of newer agents. However the current literature leaves considerable uncertainty regarding the optimal sequence, despite trials showing survival gains from triplet over doublet therapy, because rates of postprotocol therapies cannot be assessed.

    In most of the trials we studied, a PFS advantage was not translated to an OS advantage, which is likely due to the abundance of options available for treatment after progression. Upon longer follow-up, an overall survival benefit may yet be established. Poor reporting of postprotocol therapies raises the question of whether use of combination therapy rather than sequencing of multiple agents truly improves survival or overall quality of life.

    Crossover is desirable when determining whether a drug used in a latter line of therapy should be moved up front.5 As our review suggests, the low rates of subsequent use of elotuzumab and carfilzomib in the ELOQUENT-2 (elotuzumab, lenalidomide, and dexamethasone vs lenalidomide and dexamethasone)2 and ASPIRE (carfilzomib, lenalidomide, and dexamethasone vs lenalidomide and dexamethasone)3 studies in the control arm demonstrate that these agents prolong survival for patients with MM—a finding that may not have been noted had more patients received these agents in later lines of treatment in these trials. Conversely though, the poor access to these medications upon MM progression in the control arm also makes it difficult to interpret the true value of triplet over doublet therapy, because these trials can no longer answer whether a triplet strategy incorporating the novel drug in question is better than a doublet strategy in which access to these medications is provided at MM progression. We acknowledge that elotuzumab has no single agent activity and that at progression it would have to be combined with other agents. The other contemporary triplet vs doublet therapy relapsed/refractory trials, such as OPTIMISMM (pomalidomide, bortezomib, and dexamethasone vs bortezomib and dexamethasone),24 POLLUX (daratumumab, lenalidomide, and dexamethasone vs lenalidomide and dexamethasone),18 and CASTOR (daratumumab, bortezomib, and dexamethasone vs bortezomib and dexamethasone)15 have not yet reported an OS advantage, and follow-up continues. There was relatively high use of daratumumab at MM progression in the POLLUX trial (77.8% of patients with MM progression in the lenalidomide and dexamethasone arm received daratumumab at progression), and, owing to crossover, an OS advantage may not be seen.18

    When evaluating the true use of moving an agent with established efficacy in later-line treatments to an earlier line of treatment, access to the treatment on MM progression should be ensured and the trial should be powered for OS.5 Although the ALCYONE trial evaluating the addition of daratumumab to up-front therapy of bortezomib, melphalan, and prednisone has already demonstrated an OS benefit,10 only 10% of patients in the control arm received a daratumumab-containing regimen at first relapse. Two important caveats must thus be noted. First, this induction regimen is not used in the US, and second, almost all patients who have not received daratumumab as initial therapy are now expected to receive daratumumab at progression in accordance with guidelines.1 Thus, the utility of addition to daratumumab to standard up-front therapy in terms of improving overall survival remains unknown. Data from the GRIFFIN trial evaluating daratumumab, lenalidomide, bortezomib, and dexamethasone vs lenalidomide, bortezomib, and dexamethasone are immature and the trial is not powered for OS25; however, ongoing trials, such as PERSEUS,26 must ensure that daratumumab is given on MM progression and demonstrate an OS benefit to determine the true value of adding daratumumab to first-line therapy. Another commonly used regimen for newly diagnosed MM in the US is daratumumab, lenalidomide, and dexamethasone. Although data on OS are not mature, recently updated data from the MAIA trial evaluating this regimen showed that none of the 3 most commonly used regimens after MM progression for patients in the control group contained daratumumab, and all regimens were thus below the US standard of care.9

    When transparent reporting of postprotocol therapies is demonstrated, clinicians and patients can make informed decisions of the true value and sequencing of a treatment. One example is the IFM 2009 trial, where transparent reporting of postprotocol therapies allowed for optimal decision-making on the role and timing of an autologous stem cell transplant for patients with myeloma.27 Another example is the long-term follow-up of the GIMEMA-MMY-3006 study,28 which compared bortezomib, thalidomide, and dexamethasone vs thalidomide and dexamethasone as induction therapy, followed by double autologous stem cell transplant for newly diagnosed MM. With a median follow-up of 124.1 months and transparent reporting of balanced subsequent therapies in both arms, there was a clinically meaningful OS benefit for patients receiving triplet therapy induction vs a doublet therapy induction of thalidomide and dexamethasone, highlighting the value of triplet therapy as induction.

    We noted that many patients in these RCTs received no further therapy. Although reporting was inconsistent, among the trials that reported on receipt of subsequent therapy, only 54.9% of patients in frontline trials and 48.8% of patients in relapsed/refractory trials went on to receive any further line of therapy. This finding is similar to an analysis of real-world data using a nationwide database in which Fonseca et al29 reported high rates of attrition. In that study, only approximately half of the patients with newly diagnosed MM not undergoing transplant at diagnosis received a subsequent line of therapy. Considering that clinical trial patient populations are healthier than real-world patient populations and are often at institutions that have ready access to treatments if relapse occurs,30 the receipt of postprotocol therapy in our study should exceed levels seen in routine clinical practice and raises the concern that the low level reflects the limited availability of agents in multinational trial settings. This rate of attrition has led to calls to intensify the first treatment given to patients, because it may be the last treatment they receive29; however, it is unknown whether intensifying treatments alone would improve outcomes in settings where access to subsequent lines of treatment is possible or whether intensifying treatment would merely add to toxic effects.

    Limitations

    There are limitations to our study. Our search strategy included only RCTs published by December 2019. As a result, inferences on more recent practice-changing studies cannot be made. Conversely, studies that reported results in 2018 or 2019 may not have had adequate follow-up at the time our analysis was done and may yet go on to report postprotocol therapies in subsequent publications. The denominator we used for rates of subsequent therapy was based on enrolled patients, and not patients who experienced progressive MM but remained alive and able to tolerate therapy. Choice of this denominator was a necessity because trials did not report exactly how many patients had progressed and were still alive and not lost to follow-up to be eligible to receive more therapy. Clearly reporting the percentage of PFS events that were death (rather than progression) would help in future analyses. Most trial protocols do not specify posttrial therapy, so any subsequent treatments the patients receive are left to the discretion of the physician and not random assignment. Without the availability of patient-level data, it is difficult to assess exactly why the amount of postprotocol therapy was low. For patients who received no further treatment, the assessing physician may have determined no further treatment was of benefit. Owing to a lack of patient-level data, we cannot analyze the disease course and further treatment of patients who discontinued trial therapy because of progression of disease vs those who had favorable results with the trial therapy. Future RCTs can address this issue by using a dynamic treatment regimen strategy in which patients are continually randomized at decision points after the start of treatment. As an example, patients who experience adverse events are randomized to a certain strategy, whereas those who experience relapse are randomized to a different set of strategies.31

    Conclusions

    Findings in this study noted poor reporting of postprotocol therapies in MM RCTs and a high percentage of patients who received no therapy when trials report these percentages. Discrepancies between the postprotocol therapies between the 2 arms or between the therapy received and the prevailing standard of care occurred in several trials and hence precludes an understanding of the true value of treatments. Transparent reporting of postprotocol therapies should be emphasized in ongoing and future studies.

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    Accepted for Publication: March 9, 2021.

    Published: April 28, 2021. doi:10.1001/jamanetworkopen.2021.8084

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Mohyuddin GR et al. JAMA Network Open.

    Corresponding Author: Ghulam Rehman Mohyuddin, MD, Department of Hematological Malignancies and Cellular Therapeutics, Kansas University Medical Center, 2350 Shawnee Mission Pkwy, Westwood, KS 66204 (rehmanm@gmail.com).

    Author Contributions: Drs Mohyuddin and Koehn had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Mohyuddin, Koehn, Abdallah, Prasad.

    Acquisition, analysis, or interpretation of data: Mohyuddin, Koehn, Goodman.

    Drafting of the manuscript: Mohyuddin, Koehn, Abdallah, Goodman.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Mohyuddin.

    Administrative, technical, or material support: Mohyuddin, Koehn.

    Supervision: Abdallah, Prasad.

    Conflict of Interest Disclosures: Dr Goodman reported receiving consulting fees from Seattle Genetics and EUSA Pharma Consulting outside the submitted work. Dr Prasad reported receiving grants from Arnold Ventures; royalties from Johns Hopkins Press, Medscape, and Medpage; consulting fees from UnitedHealthcare; speaking fees from New Century Health and Evicore; and fees from Patreon Plenary Session podcast. No other disclosures were reported.

    Funding/Support: Arnold Ventures paid for the publication fee for this article.

    Role of the Funder/Sponsor: Arnold Ventures had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Additional Contributions: Lee Wade, MLS, BS, and Muhammad Aziz, MD (University of Toledo, Toledo, Ohio), assisted in creating the search strategy. No compensation was provided to these individuals.

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