Introduction
Dramatic advances in the treatment of multiple myeloma (MM) have led to improved outcomes. 1 Nevertheless, disease relapse is common, and patients typically require long-term ongoing treatment. These treatments can result in considerable toxic effects that negatively affect patient quality of life. 2 Multiple myeloma therapies, although effective, may be associated with unpleasant adverse effects ranging from weakness, fatigue, nausea, and diarrhea to more serious adverse events (SAEs) such as permanent neuropathy, cytopenias, life-threatening infections and bleeding events, and even death in some cases. 3 , 4 , 5 , 6 , 7 , 8 In a disease such as MM in which treatment is often given continuously over longer periods (often for years, as maintenance therapy), toxic effects and tolerability become even more important.
Clinical trial efficacy and safety results are typically reported at scientific meetings and in peer-reviewed articles. Because efficacy is often preliminarily assessed in single-group phase 2 trials, how these trials are reported becomes increasingly critical. Furthermore, as more active therapies in MM become available, the ability to understand and compare their safety profiles is becoming increasingly important to inform patient decision-making. Clinical trial investigators may increasingly use phrases that seek to minimize toxic effects, which we refer to as minimizing terms , when reporting clinical trial safety results. 9 Terms such as tolerable , manageable , and safe may be used in a subjective fashion that may not reflect the actual toxic effects of these interventions. In the absence of patient-reported outcomes (PROs), minimizing terms also may not reflect patient perceptions of whether these side effects are indeed tolerable or manageable. Patient-reported outcomes are ultimately the best way to know whether a given therapy’s toxic effects are acceptable or tolerable to patients. 10
To our knowledge, no analysis to date has assessed the use of minimizing terms within a cohort of published randomized clinical trials (RCTs). In this study of MM RCTs published between 2015 and early 2023, we estimated the prevalence of the use of minimizing terms and explored the characteristics of studies that used these terms.
Methods
For this cohort study, no direct patient information was obtained and the data used were gathered from publicly available and deidentified sources; therefore, this study was not submitted for institutional review board review in accordance with the Common Rule. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology ( STROBE ) reporting guideline for observational studies.
Data Sources
A clinical trials database and search strategy generated for a previous systematic review was used for this study. 11 We performed a search of 3 databases: PubMed, Embase, and the Cochrane Central Register of Controlled Trials. A search strategy example using Embase is highlighted in the eMethods in Supplement 1 . Briefly, the search strategy was designed to identify all MM RCTs published between January 1, 2015, and March 1, 2023. Although this search strategy included abstracts and conference proceedings, they were not included in our analysis because we limited final inclusion in this study to published articles. The search was last updated in March 1, 2023. The search strategy had no language restrictions. All other publication types, including editorials, case reports, case series, review articles, and case-control, retrospective or prospective cohort, or single-group studies, were excluded. Trials that had multiple adaptive randomizations with separate publications for each aspect of the trial were treated as separate trials.
Study Selection
In our analysis, we included only initial study reports and excluded follow-up publications or post hoc analyses. Three investigators (M.N., J.M., and G.R.M.) conducted a thorough review of the original articles and were not blinded to the study hypothesis. The search terms were predetermined, and any disputes were reviewed by all 3 investigators for clarification. This study was not separately registered on PROSPERO, as it used a data set from a previous systematic review. 11
We identified the following characteristics of the included studies: disease phase (upfront vs relapsed or refractory), study location (enrollment in 1 country vs multiple countries), and study sponsor (pharmaceutical funded vs cooperative or single-center study). We collected data on SAEs and grade 3 to 5 adverse events (AEs) from each study report as defined per each respective study. Whether PROs were presented in the publication was also recorded.
Minimizing terms were defined as subjective terms used to describe the safety profile of the intervention. We specifically looked for the terms manageable , acceptable , expected , well-tolerated , tolerable , favorable , convenient , and safe . Alternate spellings (eg, favourable ) were also included.
Statistical Analysis
The primary study outcome was the occurrence of at least 1 minimizing term in an article. We performed univariate logistic regression analyses to evaluate the association between the presence of at least 1 minimizing term and the actual incidence of grade 3 or 4 AEs, SAEs, or grade 5 AEs. Each logistic regression was restricted to articles in which the exposure variable (incidence of grade 3 or 4 AEs, SAEs, and grade 5 AEs) was nonmissing. Using the Fisher exact test of independence, we explored the association between use of at least 1 minimizing term and industry funding as well as whether PROs were reported in the article.
Statistical analysis was carried out using R, version 4.2.2 (R Project for Statistical Computing) via the RStudio integrated development environment. In addition to the core functionality of R, we used the gtsummary package, which enhances table generation and summary statistics presentation. We used 2-sided hypothesis tests, with a significance level of 5% established a priori. This significance level was used to assess the results of hypothesis tests, confidence, and any other statistical inferences made throughout the analysis. Final data analysis was performed on July 21, 2023.
Results
After excluding duplicate reports for the same trial and trials that did not meet the inclusion criteria, 65 discrete RCTs 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 were identified ( Figure 1 ). The Table highlights characteristics of the included studies.
Table.
Characteristics of Included Studies
| Study characteristic | No. (%) of studies (N = 65) |
| Sponsor | |
| Industry | 37 (57) |
| Nonindustry | 28 (43) |
| Enrollment location | |
| Multiple countries | 39 (60) |
| Limited to the US | 10 (15) |
| Limited to a single country other than the US | 16 (25) |
| Maintenance | 5 (8) |
| 2-Drug vs 3-drug | 22 (34) |
Frequency of Minimizing Terms
Of the 65 trials in this study, 56 (86%) used minimizing terms. The most frequently used minimizing terms were well-tolerated or tolerable , as observed in 29 trials (45%). Additionally, 18 trials (28%) used manageable , 16 (25%) used acceptable , 15 (23%) used expected , 15 (23%) used safe , 11 (17%) used favorable , and 9 (14%) used convenient ( Figure 2 ).
We performed an additional analysis to determine whether minimizing terms were used to describe a specific toxic effect or the general safety profile of a treatment approach. Of the 56 trials that used minimizing terms, 44 (78%) used at least 1 minimizing term that referred to toxic effects in a general sense, 11 (20%) used them to describe both the toxic effects of treatment generally and of a specific toxic effect, and 1 (2%) used them only to describe a specific toxic effect. The eTable in Supplement 1 highlights individual studies and the respective toxic effects and terms used.
AE Reporting
The frequency of SAEs was reported in 38 trials (59%). Serious adverse event rates ranged from 19% to 66% (median, 48% [IQR, 35%-56%]). There were 33 trials (87%) that used at least 1 minimizing term (median SAE rate, 48% [IQR, 34%-55%]) and 5 trials (13%) that did not use any (median SAE rate, 47% [IQR, 45%-63%]).
The overall frequency of grade 3 or 4 AEs was reported in 37 trials (57%). Grade 3 or 4 AE rates in these trials ranged from 23% to 94% (median, 75% [IQR, 59%-82%]). There were 31 trials (84%) that used at least 1 minimizing term (median grade 3 or 4 AE rate, 75% [IQR, 63%-82%]) and 6 (16%) that did not use any (median grade 3 or 4 AE rate, 57% [IQR, 36%-78%]).
The frequency of grade 5 (fatal) AEs was reported in 45 trials (69%). Grade 5 AE rates ranged from 0% to 19% (median, 3% [IQR, 1%-7%]). There were 40 trials (89%) that used at least 1 minimizing term (median grade 5 AE rate, 3% [IQR, 1%-7%]) and 5 (11%) that did not use any (median grade 5 AE rate, 1% [IQR, 1%-4%]). Among the 40 studies in which minimizing terms were used and grade 5 AEs occurred, these terms were used to describe the general treatment profile in 30 trials (75%) and were used for both general treatment safety and a specific toxic effect in 10 trials (25%). None of the minimizing terms used to describe a specific toxic effect referred to grade 5 AEs.
Association Between AE Rates and Use of Minimizing Terms
In univariate regression analysis, no association was observed between grade 3 or 4 AE rate and whether a study used minimizing terms (odds ratio [OR], 1.35 [95% CI, 0.88-2.10] per 10% AE rate increase; P = .17). Furthermore, no association was observed between use of minimizing terms and grade 5 AE rate (OR, 3.16 [95% CI, 0.27-12.7] per 10% AE rate increase; P = .45) or SAE rate (OR, 0.68 [95% CI, 0.26-1.42] per 10% SAE rate decrease; P = .35).
Association Between Industry Funding or PRO Reporting and Use of Minimizing Terms
This study included 37 industry-sponsored trials and 28 non–industry-sponsored trials. Using the Fisher exact test of independence, we explored the association between the use of at least 1 minimizing term and whether the study was industry sponsored. Among the 37 industry-sponsored studies, a higher proportion (35 [95%]) used minimizing terms. Comparatively, 21 of 28 non–industry-sponsored studies (75%) also used minimizing terms. An association was observed between the use of at least 1 minimizing term and whether a study was industry sponsored (OR, 5.68 [95% CI, 1.05-41.0]; P = .03).
We also used the Fisher exact test of independence to explore the association between the use of at least 1 minimizing term and whether the study reported PROs. Although a higher proportion of studies that did not report PROs used minimizing terms (37 of 40 [93%]) compared with those that reported PROs (19 of 25 [76%]), this difference was not statistically significant (OR, 0.26 [95% CI, 0.05-1.34]; P = .08).
Discussion
In this study of MM RCTs, we observed that most studies (86%) used minimizing terms that did not necessarily reflect the actual toxic effects of the interventions being studied. Furthermore, the use of these terms was not associated with the actual frequency of SAEs, grade 3 or 4 AEs, or grade 5 (fatal) AEs related to the treatment being studied. The industry studies examined were more likely to use minimizing terms. Only a minority of studies used PROs, yet the use of minimizing terms was widespread. Our work highlights the inherent subjectivity and lack of clarity in how toxic effects are defined and reported in the current literature.
This study builds on and updates previous work that analyzed RCTs in 5 high-impact oncology journals across all cancer types in 2018. 9 The investigators analyzed 122 trials and observed that 53 (43%) contained minimizing terms, substantially lower than the 86% observed in this study. By systematically analyzing all RCTs for a specific disease across all journals, we captured publications that may not have been subject to as rigorous or consistent a review or editing process as those in top journals. In this study, we also analyzed a longer, more recent period of trials (2015 to early 2023), highlighting that this problem continues despite awareness being raised several years ago. Furthermore, we characterized the attributes of studies that use minimizing terms and, to our knowledge, are the first to highlight that these terms were not associated with actual toxic effect rates or even treatment-related mortality. We also explored the association between use of minimizing terms and industry funding and PRO usage, both of which have important implications for future work in this space.
Our findings are especially important given that use of minimizing terms was widespread, despite scant usage of PROs. 10 Compared with investigator assessments, PROs allow patients to decide whether they consider a treatment safe or tolerable. Given that AEs tend to be underreported by clinicians compared with patients, 77 we must ask our patients if we really want to know the true toxicity profiles of our treatments. A larger sample size may reinforce our findings regarding the association between PROs and use of minimizing terms. Future trials can help address this problem by consistently reporting PROs, describing toxic effects objectively as they occur, and avoiding overemphasis of AE attribution and use of minimizing terms. Education for medical writers, who are often employed to draft reports of industry-sponsored trials, may help to curb overuse of minimizing terms. 78
Examples of studies in which toxic effects were described without minimizing terms include trials of daratumumab and elotuzumab. For example, investigators in 1 study transparently reported that daratumumab use was associated with infusion-related reactions and a higher rate of neutropenia than the control therapy, instead of using minimizing terms. 79 Another example of a trial in which toxic effects were transparently reported involved elotuzumab use in relapsed MM. 80 Such language is commendable and an example for other trials to emulate.
Limitations
This study has some limitations. Because we only analyzed RCTs, this phenomenon may be more common in early-phase nonrandomized trials and in conference presentations, which deserves further evaluation. Many studies did not report SAE rates or total grade 3 or 4 AE rates; this is a noteworthy finding that limited the statistical power of our analysis and may have led to selection bias. Given the high prevalence of minimizing terms, with the majority of articles using at least 1, our analysis had low statistical power to detect associations with various exposure variables. Thus, there may have been an association between rates of total or grade 3 or 4 AEs and use of minimizing terms that was not detected. There was no evaluation of use of other terms to describe toxic effects, and articles that used minimizing terms may also concurrently use other terms to describe such effects. The attribution of toxic effects (and death) to an intervention is inherently subjective and imperfect. 5 , 81 Our review may not have included all separate publications that contained PROs. In some cases, the term convenient may be reasonable, such as when describing the administration routes.
Conclusions
In this cohort study, we observed that trial investigators and sponsors regularly used minimizing terms to describe toxic effects in MM trials, especially in industry-sponsored studies, and this descriptive terminology did not reflect the actual rates of severe AEs or deaths in these trials. Instead of using these terms, trial investigators should highlight event rates and PROs to allow clinicians and patients to better evaluate the true tolerability of AEs.
References
1 Perrot A . How I treat frontline transplantation-eligible multiple myeloma . Blood . 2022 ; 139 ( 19 ): 2882 - 2888 . doi: 10.1182/blood.2020008735 34788422
2 Ludwig H , Delforge M , Facon T , . Prevention and management of adverse events of novel agents in multiple myeloma: a consensus of the European Myeloma Network . Leukemia . 2018 ; 32 ( 7 ): 1542 - 1560 . doi: 10.1038/s41375-018-0040-1 29720735 PMC6035147
3 Attal M , Lauwers-Cances V , Hulin C , ; IFM 2009 Study . Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma . N Engl J Med . 2017 ; 376 ( 14 ): 1311 - 1320 . doi: 10.1056/NEJMoa1611750 28379796 PMC6201242
4 Kumar SK , Harrison SJ , Cavo M , . Venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (BELLINI): a randomised, double-blind, multicentre, phase 3 trial . Lancet Oncol . 2020 ; 21 ( 12 ): 1630 - 1642 . doi: 10.1016/S1470-2045(20)30525-8 33129376
5 Cliff ERS , Reynolds G , Popat R , Teh BW , Kesselheim AS , Mohyuddin GR . Acknowledging infection risk in bispecific antibody trials in the treatment of multiple myeloma . J Clin Oncol . 2023 ; 41 ( 10 ): 1949 - 1951 . doi: 10.1200/JCO.22.02197 36716411
6 Delforge M , Ludwig H . How I manage the toxicities of myeloma drugs . Blood . 2017 ; 129 ( 17 ): 2359 - 2367 . doi: 10.1182/blood-2017-01-725705 28275090
7 Chakraborty R , Majhail NS . Treatment and disease-related complications in multiple myeloma: implications for survivorship . Am J Hematol . 2020 ; 95 ( 6 ): 672 - 690 . doi: 10.1002/ajh.25764 32086970 PMC7217756
8 Steinbach M , Julian K , McClune B , Sborov DW . Toxicity management strategies for next-generation novel therapeutics in multiple myeloma . Ther Adv Hematol . 2022 ; 13 : 20406207221100659 . doi: 10.1177/20406207221100659 35860442 PMC9289924
9 Gyawali B , Shimokata T , Honda K , Ando Y . Reporting harms more transparently in trials of cancer drugs . BMJ . 2018 ; 363 : k4383 . doi: 10.1136/bmj.k4383 30385466
10 Chakraborty R , Cannella L , Cottone F , Efficace F . Quality of patient-reported outcome reporting in randomised controlled trials of haematological malignancies according to international quality standards: a systematic review . Lancet Haematol . 2020 ; 7 ( 12 ): e892 - e901 . doi: 10.1016/S2352-3026(20)30292-1 33242446
11 Mohyuddin GR , Koehn K , Abdallah AO , . Use of endpoints in multiple myeloma randomized controlled trials over the last 15 years: a systematic review . Am J Hematol . 2021 ; 96 ( 6 ): 690 - 697 . doi: 10.1002/ajh.26166 33735453
12 Velcade, thalidomide, and dexamethasone versus velcade and dexamethasone versus velcade, melphalan, and prednisone (UPFRONT). ClinicalTrials.gov identifier: NCT00507416 . Updated May 1, 2014 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT00507416?cond=NCT00507416&rank=1&tab=table
13 A phase 1b/2, dose-escalation study of elotuzumab (humanized anti-CS1 monoclonal IgG1 antibody) in relapsed multiple myeloma. ClinicalTrials.gov identifier: NCT00742560 . Updated October 1, 2018 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT00742560?term=NCT00742560&rank=1
14 A study of combination of daratumumab and velcade (bortezomib) melphalan-prednisone (DVMP) compared to velcade melphalan-prednisone (VMP) in participants with previously untreated multiple myeloma. ClinicalTrials.gov identifier: NCT02195479 . Updated October 12, 2023 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT02195479?term=NCT02195479&rank=1
15 Study of lenalidomide and dexamethasone with or without pembrolizumab (MK-3475) in participants with newly diagnosed treatment naive multiple myeloma (MK-3475-185/KEYNOTE-185). ClinicalTrials.gov identifier: NCT02579863 . Updated July 20, 2021 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT02579863?term=NCT02579863&rank=1
16 Stem cell transplant with lenalidomide maintenance in patients with multiple myeloma (BMT CTN 0702). ClinicalTrials.gov identifier: NCT01109004 . Updated December 9, 2021 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT01109004?term=NCT01109004&rank=1
17 Aplidin-dexamethasone in relapsed/refractory myeloma (ADMYRE). ClinicalTrials.gov identifier: NCT01102426 . Updated November 10, 2020 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT01102426?term=NCT01102426&rank=1
18 Bortezomib (Velcade®), lenalidomide (Revlimid®) and IV busulfan (Busilvex®) in patients under 65 years old (GEM2012MENOS65). ClinicalTrials.gov identifier: NCT01916252 . Updated September 27, 2017 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT01916252?term=NCT01916252&rank=1
19 A study to evaluate daratumumab in transplant eligible participants with previously untreated multiple myeloma (Cassiopeia). ClinicalTrials.gov identifier: NCT02541383 . Updated December 7, 2020 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT02541383?term=NCT02541383&rank=1
20 Safety and efficacy of pomalidomide. bortezomib and low-dose dexamethasone in subjects with relapsed or refractory multiple myeloma (OPTIMISMM). ClinicalTrials.gov identifier: NCT01734928 . Updated June 6, 2023 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT01734928?term=NCT01734928&rank=1
21 Study of pomalidomide and low dose dexamethasone with or without pembrolizumab (MK-3475) in refractory or relapsed and refractory multiple myeloma (rrMM) (MK-3475-183/KEYNOTE-183). ClinicalTrials.gov identifier: NCT02576977 . Updated October 8, 2021 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT02576977?term=NCT02576977&rank=1
22 A study comparing daratumumab, lenalidomide, and dexamethasone with lenalidomide and dexamethasone in relapsed or refractory multiple myeloma. ClinicalTrials.gov identifier: NCT02076009 . Updated October 12, 2023 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT02076009?term=NCT02076009&rank=1
23 Velcade (bortezomib) consolidation after transplant (VCAT). ClinicalTrials.gov identifier: NCT01539083 . Updated December 27, 2018 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT01539083?term=NCT01539083&rank=1
24 Phase 3 study of carfilzomib, melphalan, prednisone vs bortezomib, melphalan, prednisone in newly diagnosed multiple myeloma (CLARION). ClinicalTrials.gov identifier: NCT01818752 . Updated August 26, 2019 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT01818752?term=NCT01818752&rank=1
25 Study comparing daratumumab, lenalidomide, and dexamethasone with lenalidomide and dexamethasone in participants with previously untreated multiple myeloma. ClinicalTrials.gov identifier: NCT02252172 . Updated October 12, 2023 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT02252172?term=NCT02252172&rank=1
26 Phase III study of lenalidomide and dexamethasone with or without elotuzumab to treat relapsed or refractory multiple myeloma (ELOQUENT - 2). ClinicalTrials.gov identifier: NCT01239797 . Updated June 1, 2022 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT01239797
27 Phase 3 study with carfilzomib and dexamethasone versus bortezomib and dexamethasone for relapsed multiple myeloma patients (ENDEAVOR). ClinicalTrials.gov identifier: NCT01568866 . Updated November 14, 2022 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT01568866?term=NCT01568866&rank=1
28 A randomized trial to compare busulfan + melphalan 140 mg/m 2 with melphalan 200 mg/m 2 as preparative regimen for autologous hematopoietic stem cell transplantation for multiple myeloma. ClinicalTrials.gov identifier: NCT01413178 . Updated April 21, 2020 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT01413178?term=NCT01413178&rank=1
29 Study to evaluate optimized retreatment and prolonged therapy with bortezomib (OPTIMRETREAT). ClinicalTrials.gov identifier: NCT01910987 . Updated February 17, 2017 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT01910987?term=NCT01910987&rank=1
30 Addition of daratumumab to combination of bortezomib and dexamethasone in participants with relapsed or refractory multiple myeloma. ClinicalTrials.gov identifier: NCT02136134 . Updated October 12, 2023 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT02136134?term=NCT02136134&rank=1
31 Once-weekly versus twice-weekly carfilzomib in combination with dexamethasone in adults with relapsed and refractory multiple myeloma. ClinicalTrials.gov identifier: NCT02412878 . Updated September 23, 2022 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT02412878?term=NCT02412878&rank=1
32 A study of carfilzomib vs best supportive care in subjects with relapsed and refractory multiple myeloma (FOCUS). ClinicalTrials.gov identifier: NCT01302392 . Updated June 02, 2017 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT01302392?term=NCT01302392&rank=1
33 Lenalidomide and dexamethasone with or without bortezomib in treating patients with previously untreated multiple myeloma. ClinicalTrials.gov identifier: NCT00644228 . Updated September 13, 2023 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT00644228?term=NCT00644228&rank=1
34 Study comparing conventional dose combination RVD to high-dose treatment with ASCT in the initial myeloma up to 65 years (IFM/DFCI2009). ClinicalTrials.gov identifier: NCT01191060 . Updated April 18, 2019 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT01191060?term=NCT01191060&rank=1
35 Moreau P , Masszi T , Grzasko N , ; TOURMALINE-MM1 Study Group . Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma . N Engl J Med . 2016 ; 374 ( 17 ): 1621 - 1634 . doi: 10.1056/NEJMoa1516282 27119237
36 Moreau P , Hulin C , Macro M , . VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial . Blood . 2016 ; 127 ( 21 ): 2569 - 2574 . doi: 10.1182/blood-2016-01-693580 27002117
37 Lenalidomide and dexamethasone versus melphalan prednisone and lenalidomide versus cyclophosphamide, prednisone and lenalidomide in elderly multiple myeloma patients. ClinicalTrials.gov identifier: NCT01093196 . Updated July 03, 2023 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT01093196?term=NCT01093196&rank=1
38 Iberoamerican protocol with thalidomide in patients with symptomatic newly diagnosed multiple myeloma over 65 years. ClinicalTrials.gov identifier: NCT01532856 . Updated February 15, 2012 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT01532856?term=NCT01532856&rank=1
39 Cyclophosphamide, lenalidomide and dexamethasone (CRD) versus melphalan (200 mg/m 2 ) followed by autologous stem cell transplant (ASCT) in newly diagnosed multiple myeloma subjects. ClinicalTrials.gov identifier: NCT01091831 . Updated July 3, 2023 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT01091831?cond=NCT01091831&rank=1
40 Study comparing daratumumab, lenalidomide, bortezomib, and dexamethasone (D-RVd) versus lenalidomide, bortezomib, and dexamethasone (RVd) in subjects with newly diagnosed multiple myeloma. ClinicalTrials.gov identifier: NCT02874742 . Updated July 27, 2023 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT02874742?term=NCT02874742&rank=1
41 A study of subcutaneous versus (vs.) intravenous administration of daratumumab in participants with relapsed or refractory multiple myeloma. ClinicalTrials.gov identifier: NCT03277105 . Updated October 11, 2023 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT03277105?term=NCT03277105&rank=1
42 Study to compare VMP with HDM followed by VRD consolidation and lenalidomide maintenance in patients with newly diagnosed multiple myeloma (HO95). ClinicalTrials.gov identifier: NCT01208766 . Updated August 22, 2023 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT01208766?term=NCT01208766&rank=1
43 A study evaluating venetoclax (ABT-199) in multiple myeloma subjects who are receiving bortezomib and dexamethasone as standard therapy (Bellini). ClinicalTrials.gov identifier: NCT02755597 . Updated August 22, 2023 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT02755597?term=NCT02755597&rank=1
44 Phase II study of lenalidomide/dexamethasone with or without elotuzumab for newly diagnosed MM patients in Japan. ClinicalTrials.gov identifier: NCT02272803 . Updated June 22, 2023 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT02272803?term=NCT02272803&rank=1
45 Study of bortezomib and dexamethasone with or without elotuzumab to treat relapsed or refractory multiple myeloma. ClinicalTrials.gov identifier: NCT01478048 . Updated May 21, 2018 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT01478048?term=NCT01478048&rank=1
46 Pomalidomide in combination with high dose dexamethasone and oral cyclophosphamide. ClinicalTrials.gov identifier: NCT01432600 . Updated May 23, 2017 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT01432600?term=NCT01432600&rank=1
47 Melphalan and amifostine followed by one or two autologous or syngeneic stem cell transplants and maintenance therapy in treating patients with stage II-III multiple myeloma. ClinicalTrials.gov identifier: NCT00217438 . Updated August 21, 2015 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT00217438
48 Multinational clinical study comparing isatuximab, pomalidomide, and dexamethasone to pomalidomide and dexamethasone in refractory or relapsed and refractory multiple myeloma patients (ICARIA-MM). ClinicalTrials.gov identifier: NCT02990338 . Updated August 01, 2023 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT02990338?term=NCT02990338&rank=1
49 Multinational clinical study comparing isatuximab, carfilzomib and dexamethasone to carfilzomib and dexamethasone in relapse and/or refractory multiple myeloma patients (IKEMA). ClinicalTrials.gov identifier: NCT03275285 . Updated May 16, 2023 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT03275285?term=NCT03275285&rank=1
50 Study of carfilzomib, daratumumab and dexamethasone for patients with relapsed and/or refractory multiple myeloma (CANDOR). ClinicalTrials.gov identifier: NCT03158688 . Updated May 12, 2023 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT03158688?term=NCT03158688&rank=1
51 A study of oral ixazomib maintenance therapy in participants with newly diagnosed multiple myeloma (NDMM) not treated with stem cell transplantation (SCT). ClinicalTrials.gov identifier: NCT02312258 . Updated September 21, 2023 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT02312258?term=NCT02312258&rank=1
52 Comparison of pomalidomide and dexamethasone with or without daratumumab in subjects with relapsed or refractory multiple myeloma previously treated with lenalidomide and a proteasome inhibitor daratumumab/pomalidomide/dexamethasone vs pomalidomide/dexamethasone (EMN14). ClinicalTrials.gov identifier: NCT03180736 . Updated May 11, 2023 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT03180736?term=NCT03180736&rank=1
53 Bortezomib, selinexor, and dexamethasone in patients with multiple myeloma (BOSTON). ClinicalTrials.gov identifier: NCT03110562 . Updated January 26, 2023 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT03110562?term=NCT03110562&rank=1
54 Bortezomib or carfilzomib with lenalidomide and dexamethasone in treating patients with newly diagnosed multiple myeloma. ClinicalTrials.gov identifier: NCT01863550 . Updated June 15, 2023 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT01863550?term=NCT01863550&rank=1
55 A study to compare daratumumab, bortezomib, and dexamethasone (DVd) vs bortezomib and dexamethasone (Vd) in Chinese participants with relapsed or refractory multiple myeloma. ClinicalTrials.gov identifier: NCT03234972 . Updated October 12, 2023 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT03234972?term=NCT03234972&rank=1
56 Panobinostat/bortezomib/dexamethasone in relapsed or relapsed-and-refractory multiple myeloma (PANORAMA_3). ClinicalTrials.gov identifier: NCT02654990 . Updated July 14, 2023 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT02654990?term=NCT02654990&rank=1
57 Trial of carfilzomib, lenalidomide, dexamethasone versus lenalidomide alone after stem-cell transplant for multiple myeloma. ClinicalTrials.gov identifier: NCT02659293 . Updated April 28, 2023 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT02659293?term=NCT02659293&rank=1
58 Study to determine the efficacy and safety of standard schedule versus a new algorithm of dose reductions in elderly and unfit newly diagnosed multiple myeloma patients receiving lenalidomide plus steroids. ClinicalTrials.gov identifier: NCT02215980 . Updated June 29, 2023 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT02215980?term=NCT02215980&rank=1
59 Trial on the effect of isatuximab to lenalidomide/bortezomib/dexamethasone (RVd) induction and lenalidomide maintenance in patients with newly diagnosed myeloma (GMMG HD7). ClinicalTrials.gov identifier: NCT03617731 . Updated May 12, 2023 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT03617731?term=NCT03617731&rank=1
60 Randomized trial of lenalidomide, bortezomib, dexamethasone vs high-dose treatment with SCT in MM patients up to age 65 (DFCI 10-106). ClinicalTrials.gov identifier: NCT01208662 . Updated April 19, 2023 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT01208662?term=NCT01208662&rank=1
61 Bortezomib-melphalan conditioning regimen vs melphalan for frontline transplant eligible patients with multiple myeloma (IFM2014-02). ClinicalTrials.gov identifier: NCT02197221 . Updated May 23, 2022 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT02197221?term=NCT02197221&rank=1
62 A study of melphalan flufenamide (melflufen)-dex or pomalidomide-dex for RRMM patients refractory to lenalidomide (OCEAN). ClinicalTrials.gov identifier: NCT03151811 . Updated June 28, 2023 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT03151811?term=NCT03151811&rank=1
63 Phase II study of IRD (ixazomib, lenalidomide, dexamethasone) post autologous stem cell transplantation followed by maintenance ixazomib or lenalidomide for multiple myeloma. ClinicalTrials.gov identifier: NCT02253316 . Updated August 1, 2023 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT02253316?term=NCT02253316&rank=1
64 Trial of carfilzomib, lenalidomide, dexamethasone versus lenalidomide alone after stem-cell transplant for multiple myeloma. ClinicalTrials.gov identifier: NCT02253316 . Updated April 28, 2023 . Accessed September 10, 2023. https://clinicaltrials.gov/study/NCT02659293?term=NCT02659293&rank=1
65 Jackson GH , Davies FE , Pawlyn C , ; UK NCRI Haemato-oncology Clinical Studies Group . Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (myeloma XI): a multicentre, open-label, randomised, phase 3 trial . Lancet Oncol . 2019 ; 20 ( 1 ): 57 - 73 . doi: 10.1016/S1470-2045(18)30687-9 30559051 PMC6318225
66 A randomized comparison of thalidomide and lenalidomide combinations in myeloma patients of all ages. ISRCTN Registry identifier: ISRCTN49407852. Updated April 21, 2023 . Accessed September 10, 2023. https://www.isrctn.com/ISRCTN49407852
67 Jenner MW , Pawlyn C , Davies FE , ; UK National Cancer Research Institute (NCRI) Haemato-oncology Clinical Studies Group . The addition of vorinostat to lenalidomide maintenance for patients with newly diagnosed multiple myeloma of all ages: results from ‘Myeloma XI’, a multicentre, open-label, randomised, phase III trial . Br J Haematol . 2023 ; 201 ( 2 ): 267 - 279 . doi: 10.1111/bjh.18600 36541152 PMC10952726
68 Lenalidomide and dexamethasone with or without high-dose melphalan and autologous blood stem cell transplantation followed by lenalidomide maintenance in the treatment of relapsed multiple myeloma. ISRCTN Registry identifier: ISRCTN16345835. Updated October 6, 2016 . Accessed September 10, 2023. https://www.isrctn.com/ISRCTN16345835?q=ISRCTN16345835&filters=&sort=&offset=1&totalResults=1&page=1&pageSize=10
69 Montefusco V , Corso A , Galli M , . Bortezomib, cyclophosphamide, dexamethasone versus lenalidomide, cyclophosphamide, dexamethasone in multiple myeloma patients at first relapse . Br J Haematol . 2020 ; 188 ( 6 ): 907 - 917 . doi: 10.1111/bjh.16287 31898319
70 Goldschmidt H , Mai EK , Dürig J , ; German-speaking Myeloma Multicenter Group (GMMG) . Response-adapted lenalidomide maintenance in newly diagnosed myeloma: results from the phase III GMMG-MM5 trial . Leukemia . 2020 ; 34 ( 7 ): 1853 - 1865 . doi: 10.1038/s41375-020-0724-1 32034285
71 Zweegman S , van der Holt B , Mellqvist UH , . Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma . Blood . 2016 ; 127 ( 9 ): 1109 - 1116 . doi: 10.1182/blood-2015-11-679415 26802176
72 Jacobus SJ , Rajkumar SV , Weiss M , . Randomized phase III trial of consolidation therapy with bortezomib-lenalidomide-dexamethasone (VRd) vs bortezomib-dexamethasone (Vd) for patients with multiple myeloma who have completed a dexamethasone based induction regimen . Blood Cancer J . 2016 ; 6 ( 7 ): e448 . doi: 10.1038/bcj.2016.55 27471864 PMC5030380
73 Mai EK , Bertsch U , Dürig J , . Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma . Leukemia . 2015 ; 29 ( 8 ): 1721 - 1729 . doi: 10.1038/leu.2015.80 25787915
74 Zweegman S , Stege CAM , Haukas E , . Ixazomib-Thalidomide-low dose dexamethasone induction followed by maintenance therapy with ixazomib or placebo in newly diagnosed multiple myeloma patients not eligible for autologous stem cell transplantation; results from the randomized phase II HOVON-126/NMSG 21.13 trial . Haematologica . 2020 ; 105 ( 12 ): 2879 - 2882 . doi: 10.3324/haematol.2019.240374 33256392 PMC7716358
75 Jackson GH , Pawlyn C , Cairns DA , ; UK NCRI Haemato-oncology Clinical Studies Group . Carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) as induction therapy for transplant-eligible, newly diagnosed multiple myeloma patients (Myeloma XI+): interim analysis of an open-label randomised controlled trial . PLoS Med . 2021 ; 18 ( 1 ): e1003454 . doi: 10.1371/journal.pmed.1003454 33428632 PMC7799846
76 Fenk R , Giagounidis A , Goldschmidt H , . Efficacy and tolerability of high- versus low-dose lenalidomide maintenance therapy of multiple myeloma after autologous blood stem cell transplantation . Clin Cancer Res . 2020 ; 26 ( 22 ): 5879 - 5886 . doi: 10.1158/1078-0432.CCR-20-0841 32817078
77 Basch E , Jia X , Heller G , . Adverse symptom event reporting by patients vs clinicians: relationships with clinical outcomes . J Natl Cancer Inst . 2009 ; 101 ( 23 ): 1624 - 1632 . doi: 10.1093/jnci/djp386 19920223 PMC2786917
78 Buck E , Haslam A , Tuia J , Prasad V . Frequency and characteristics of trials using medical writer support in high-impact oncology journals . JAMA Netw Open . 2023 ; 6 ( 2 ): e2254405 . doi: 10.1001/jamanetworkopen.2022.54405 36723940 PMC9892954
79 Dimopoulos MA , Oriol A , Nahi H , ; POLLUX Investigators . Daratumumab, lenalidomide, and dexamethasone for multiple myeloma . N Engl J Med . 2016 ; 375 ( 14 ): 1319 - 1331 . doi: 10.1056/NEJMoa1607751 27705267
80 Lonial S , Dimopoulos M , Palumbo A , ; ELOQUENT-2 Investigators . Elotuzumab therapy for relapsed or refractory multiple myeloma . N Engl J Med . 2015 ; 373 ( 7 ): 621 - 631 . doi: 10.1056/NEJMoa1505654 26035255
81 Hillman SL , Mandrekar SJ , Bot B , . Evaluation of the value of attribution in the interpretation of adverse event data: a North Central Cancer Treatment Group and American College of Surgeons Oncology Group investigation . J Clin Oncol . 2010 ; 28 ( 18 ): 3002 - 3007 . doi: 10.1200/JCO.2009.27.4282 20479400 PMC2903334
eTable. Included Randomized Clinical Trials
eMethods. Example Search Strategy on Embase
Click here for additional data file.
Data Sharing Statement
Click here for additional data file.