Real-world treatment trends and triple class exposed status in newly diagnosed multiple myeloma patients in Japan: A retrospective claims database study

Toyoki Moribe; Linghua Xu; Kazumi Take; Naohiro Yonemoto; Kenshi Suzuki

doi:10.1371/journal.pone.0310333

Peer Review History

Original SubmissionJune 24, 2024
17 Jul 2024 Decision Letter - Mehmet Baysal, Editor PONE-D-24-24880Real-world treatment trends and triple class exposed status in newly diagnosed multiple myeloma patients in Japan: a retrospective claims database study.PLOS ONE Dear Dr. Moribe, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. The authors has to be state more clearly the manuscirpt and they could arrange their data more effectively.Some part is really hard to follow and cope. Please submit your revised manuscript by Aug 31 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Mehmet Baysal Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. Thank you for stating the following in the Competing Interests section: "I have read the journal's policy and the authors of this manuscript have the following competing interests: Toyoki Moribe, Linghua Xu, Kazumi Take, and Naohiro Yonemoto are employees of Pfizer Japan Inc., a sponsor of this study. Statistical analysis support was provided by Tatsuo Sakashita and Takayuki Sawada of Clinical Study Support, Inc. (Nagoya, Japan), which was funded by Pfizer Japan Inc." We note that one or more of the authors are employed by a commercial company: Pfizer Japan Inc. a. Please provide an amended Funding Statement declaring this commercial affiliation, as well as a statement regarding the Role of Funders in your study. If the funding organization did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries and/or research materials, please review your statements relating to the author contributions, and ensure you have specifically and accurately indicated the role(s) that these authors had in your study. You can update author roles in the Author Contributions section of the online submission form. Please also include the following statement within your amended Funding Statement. “The funder provided support in the form of salaries for authors [insert relevant initials], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.” If your commercial affiliation did play a role in your study, please state and explain this role within your updated Funding Statement. b. Please also provide an updated Competing Interests Statement declaring this commercial affiliation along with any other relevant declarations relating to employment, consultancy, patents, products in development, or marketed products, etc. Within your Competing Interests Statement, please confirm that this commercial affiliation does not alter your adherence to all PLOS ONE policies on sharing data and materials by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests) . If this adherence statement is not accurate and there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. Please include both an updated Funding Statement and Competing Interests Statement in your cover letter. We will change the online submission form on your behalf. 3. For studies involving third-party data, we encourage authors to share any data specific to their analyses that they can legally distribute. PLOS recognizes, however, that authors may be using third-party data they do not have the rights to share. When third-party data cannot be publicly shared, authors must provide all information necessary for interested researchers to apply to gain access to the data. (https://journals.plos.org/plosone/s/data-availability#loc-acceptable-data-access-restrictions) For any third-party data that the authors cannot legally distribute, they should include the following information in their Data Availability Statement upon submission: 1) A description of the data set and the third-party source 2) If applicable, verification of permission to use the data set 3) Confirmation of whether the authors received any special privileges in accessing the data that other researchers would not have 4) All necessary contact information others would need to apply to gain access to the data [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Partly Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: No Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: No Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Article title: 2 Real-world treatment trends and triple class exposed status in newly diagnosed multiple myeloma patients 3 in Japan: a retrospective claims database study. In this manuscript, Moribe et al. describe the current treatment trends for patients with NDMM in Japan. The study does a good job of describing the regimens used across lines of therapy in both transplant-eligible and transplant-ineligible patients. It also describes the treatment trends according to underlying characteristics and comorbidities, which are useful for clinicians at the time of treatment selection. They also describe the percentage of triple-class exposed (TCE) patients across treatment lines. My main concerns are outlined below. Title: does not match with the manuscript as a whole. The authors discuss NDMM and RRMM. Perhaps the authors should consider a more broad title like A retrospective study to define treatment patterns for patients in Japan with newly diagnosed and relapsed and refractory multiple myeloma. Abstract: A bit all over the place. • The authors need to comment as to why of the 1780 patients, why only 128 were considered transplant eligible. Why did they not include more transplant eligible patients? • They majority of the abstract is focused on the NDMM patients and not RRMM. • How is it that by the 5th line that only 21.2% and 43.8% of patients were triple class exposed? Line 70: This sentence does not make any sense and should be rewritten. Line 74: It is untrue that triple class exposed patients have limited treatment options. Almost all patients will have been triple class exposed by the end of 2nd line therapy (at the very latest) and most will be TCE during early induction. Are the authors considering TCE to be equivalent to triple class refractory (TCR). If so, this needs to be changed throughout the manuscript. Additionally, with the addition of CAR and bispecifics, treatment options are now considerably more than they were even a few years ago - this should be highlighted. Line 114: It is important to highlight the time period in which patients had data collected and not just when the data was captured. The results suggest that patients treated with an initial diagnosis before 2015 were included. This is unclear. Line 119-120 – Should read “ Patients were excluded from the study if they were prescribed anti-myeloma treatment drugs other than dexamethasone and prednisone before index date” Line 124 – The definition of index date should be moved up to before the concept is first utilized (page 6 line 120). To make it easier for the reader. Line 150 – Authors mentioned that the number of transfusions was a variable of interest, but this was never addressed. Page 9; Study population – Although Figure 1 does a great job at explaining the breakdown of patients, the text is a little confusing and should be rewritten. Line 188: Again, this is a very skewed population. Is autoHSCT not standarly used in Japan? Line 198+: How are comorbidities defined. If this data is included, the authors need to explain what is meant by renal dysfunction, etc (e.g. CrCl between X and Y) Table 4 - It is not clear to me what the difference between the cumulative number and proportion of patients using therapies across different treatment lines and the number and proportion of patients based on the most recent treatment lines being used is, this needs further explanation. Table 5: This table is unclear and confusing. It is not clear how duration of treatment in 1st line treatment is broken down between patients prescribed and not prescribed subsequent treatment. Are you saying that duration of treatment to 1st line (non-transplant) in those patients treated with more than one line of therapy was 6.9 months vs 14.3 months in those patients that didn't get more than one line of treatment? Table 6 - It would be more visually impactful if the table were reorganized to display the treatment regimens for the non-transplant and the transplant groups side by side rather than in sequential order, similar to Table 7. "Frequently used treatment regimen": The first paragraph in this section needs clarity. The data is not presented in a way that is useful or informative. The table helps clarify this a bit but the authors should consider rewriting this section so that it is more clear. Additionally, in Table 6, the authors include IRd - has ixazomib been introducted anywhere in the manuscript? What about F, Sar, S, etc.? Consider moving all of the regimens that are not discussed in the body of the manuscript to the supplemental section. Line 244: 24.7, 23.8, and 15.6 don't add up to 100%. What else were patients treated with? I thought the inclusion was that patients had to be treated with len, bort, or a combination of these. Line 247: Not sure this makes sense. 24.7% of patients received Rd in 1st line and then 22% received Rd in the 2nd line. It would be more useful to understand the treatment pattern in my opinion. For example, did physicians change from Rd to Vd or Rd to RVd? Line 261: Top 3? Perhaps use wording like the three more frequently prescribed. Line 281: "in the TCE situation" should be rewritten Table 7: Again, I am confused how any patients in the 4th or 5th line could not be triple class exposed. Also, with the attrition rate being so high, is cumulative TCE meaningful? Line 294: This paragraph needs to be cleaned up, the description is not very clear though the information is important. Line 315: Need to discuss why more transplant patients were not captured in this data set. Lines 348-350 – The authors comment on utilizing K vs V in the second line mostly because of the difference in adverse events (namely peripheral neuropathy) – However, there should also be a mention of the difference in efficacy of K vs. V and also that as they clearly described nearly 50% of patients received bortezomib in the first line, making carfilzomib a better PI option in the second and further lines. Line 357 onwards – The authors’ comment mentioned that “Lenalidomide containing regimens should be generally avoided because of their characteristic side effects, DVT and renal excretion pathway.” – This should be addressed as there is evidence that lenalidomide can be utilized in patients with renal dysfunction even in those undergoing HD as long as the dose is adjusted to the Creatinine Clearance. This statement might wrongly prevent providers from using lenalidomide, which, as we know, is a cornerstone of MM treatment in patients with any degree of renal dysfunction. Similarly, the authors also mentioned, “On the other hand, in patients with cardiac and pulmonary dysfunctions, Vd should be avoided because bortezomib was characterized by cardiac and pulmonary toxicities.” – In the ENDURANCE trial, only 5% of patients experienced at least one grade 2 or higher CV and pulmonary AE, and in most cases these were reversible. This statement could also wrongly lead clinicians to avoid bortezomib in patients with any degree of cardiopulmonary disease and should be modified. Discussion: Much too long, this needs to be shortened and written more concisely. A segment focusing on proposing the standardization of quadruplet therapy in NDMM should be added – if this aligns with the resources and available drug approval in Japan. Conclusion: Sentences 1 and 2 in this paragraph are not the reason for this study and this data was not highlighted in the manuscript, so why do the authors include it here? Reviewer #2: Thanks to the authors for the article. A useful study reflecting real life data. The study nicely discussed the treatments applied to patients diagnosed with multiple myeloma in Japan. I am just wondering why there is a significant difference in the number of transplant-ineligible and transplant-eligible patients. ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0310333.r001
Revision 1
12 Aug 2024 Author Response Reviewers' comments: Reviewer's Responses to Questions Comments to the Author Thank you for your kind overall evaluation and your valuable time spent on reviewing our manuscript. We have answered your comments below and revised the manuscript accordingly. In addition, we have also revised according to comments from reviewers and made some corrections based on fact-check. 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Partly Reviewer #2: Yes Response: We have made minor revisions of the conclusion based on the data presented in this study as below. “Our study showed that in the real-world setting, transplantation can be performed in patients with fewer comorbidities, aged up to 73 years. The present study showed that most transplant patients were hospitalized in large hospitals. In both non-transplant and transplant patients receiving 1st-line treatment, most received an Rd-based or Vd-based doublet regimen, or an RVd-based triplet regimen. Most TCE patients had received DRd-based, RVd-based, or DVd-based regimens. The proportion of TCE patients showed an increasing trend after 2nd or later lines for both non-transplant and transplant patients; this was highest in the transplant group. The findings of this study will support the development of treatment strategies and policies for MM treatment in real-world clinical practice in Japan.” (Page 27 of the track file of the revised manuscript) _______________________________________ 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: No Reviewer #2: Yes Response: In this study the data were summarized descriptively. The patient characteristics, duration of treatment, treatment pattern, and other variables in transplanted and non-transplanted patients who are newly diagnosed with MM were evaluated descriptively with summary statistics. This set of analyses is intended mainly for descriptive purposes and to provide a basis for future studies. P-values were not calculated to investigate any prespecified set of hypotheses. Further, all data analysis was performed using statistical software SAS version 9.4 (SAS Institute, Cary, NC, USA). We have already included all these details in the statistical analysis section in the manuscript file. (Last paragraph of statistical analysis section on Page 9 of the track file of the revised manuscript) ________________________________________ 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes Response: Thank you for your review and confirmation. ________________________________________ 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: No Reviewer #2: Yes Response: We have carefully looked over the manuscript and made some corrections for the language and consistency as below. We have got the manuscript edited by a native English editor as well and editor has made editorial changes throughout the manuscript. These changes are shown as track changes in the track version of the revised manuscript file. _______________________________________ 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Article title: Real-world treatment trends and triple class exposed status in newly diagnosed multiple myeloma patients in Japan: a retrospective claims database study. In this manuscript, Moribe et al. describe the current treatment trends for patients with NDMM in Japan. The study does a good job of describing the regimens used across lines of therapy in both transplant-eligible and transplant-ineligible patients. It also describes the treatment trends according to underlying characteristics and comorbidities, which are useful for clinicians at the time of treatment selection. They also describe the percentage of triple-class exposed (TCE) patients across treatment lines. My main concerns are outlined below. Response: We greatly appreciate your positive feedback. Moreover, we also thank you for your kind advice and review comments. Here we are providing a point-by-point response. 1) Title: does not match with the manuscript as a whole. The authors discuss NDMM and RRMM. Perhaps the authors should consider a more broad title like A retrospective study to define treatment patterns for patients in Japan with newly diagnosed and relapsed and refractory multiple myeloma. Response: Thank you for your suggestion. As you pointed out, the results include data for both NDMM and RRMM patients. However, this study mainly focused on NDMM patients rather than RRMM patients after strict definition of NDMM patients. Moreover, as for RRMM setting, the data has just been presented as the treatment trend and TCE status among NDMM patients receiving 2nd, 3rd, 4th, and 5th or later lines of treatments. Therefore, we would like to keep the title unchanged. 2) Abstract: A bit all over the place. • The authors need to comment as to why of the 1780 patients, why only 128 were considered transplant eligible. Why did they not include more transplant eligible patients? • They majority of the abstract is focused on the NDMM patients and not RRMM. • How is it that by the 5th line that only 21.2% and 43.8% of patients were triple class exposed? Response: • This is a limitation of this study. As Japanese patients with MM are very elderly (with median age >75 years) and have multiple comorbidities, only 20% of NDMM patients are eligible for transplantation. Furthermore, in this study, NDMM patients who had a follow-up period of ≥6 months from the index date have been selected. When the patients had shorter follow-up period, the medical record for transplantation might not be detected even if the patients have received transplantation after the follow-up period in this study. Therefore, the number of transplant eligible patients may be underestimated. • As you pointed out, this study focused mainly on NDMM patients rather than RRMM patients. • The NDMM patients have been first identified according to inclusion and exclusion criteria and then evaluated the TCE situation in each treatment line for the patients. However, because the follow-up period was ≥6 months from the index date, more than half of the NDMM patients remained in the 2nd line. Just a few patients transferred up to the 5th line. Thus, the MM patient number has gradually become less from the 1st line to the 5th line, though the TCE patient number has gradually increased from the 1st line to the 5th line. Therefore, the cumulative TCE patients in the 5th line may be underestimated. 3) Line 70: This sentence does not make any sense and should be rewritten. Response: According to your comment, we have rewritten the sentence as below. “However, daratumumab combination regimens used in the 1st line have complicated MM treatment and fragmented later-line MM treatment sequences.” (Last three lines of first paragraph on Page 4 of the track file of the revised manuscript) 4) Line 74: It is untrue that triple class exposed patients have limited treatment options. Almost all patients will have been triple class exposed by the end of 2nd line therapy (at the very latest) and most will be TCE during early induction. Are the authors considering TCE to be equivalent to triple class refractory (TCR). If so, this needs to be changed throughout the manuscript. Additionally, with the addition of CAR and bispecifics, treatment options are now considerably more than they were even a few years ago - this should be highlighted. Response: As you pointed out, most patients will have been TCE by the end of 2nd line therapy most recently, since DRd and D-VMP regimens have been integrated in the 1st line. However, because the study period was from January 1, 2015 to December 31, 2022, the most patients in this study should have been TCE in later lines than the 2nd line. We have added this information into the description as below: “Our results suggested that there was an increasing trend in the proportion of TCE patients, especially in transplant group patients (cumulative TCE rate; 21.2% and 43.8% in the non-transplant and transplant groups, respectively). Since DRd and D-VMP regimens have been integrated into 1st-line treatment, most patients are now TCE by the end of 2nd-line therapy. However, because the study period was from January 1, 2015 to December 31, 2022, the most patients in the study should have been TCE in later lines than the 2nd line.” (Second paragraph on Page 25 of the track file of the revised manuscript) Further, we consider TCE is not equivalent to TCR. Most patients with MM who are TCE will eventually have relapse and TCE patients who have relapsed or are refractory may have a poor prognosis with worsening outcomes and limited treatment options in clinical practice considering the physical condition of patients. Below are the references: • Gandhi UH, Cornell RF, Lakshman A et al. Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia 33(9), 2266–2275 (2019). • Kumar SK, Dimopoulos MA, Kastritis E et al. Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study. Leukemia 31(11), 2443–2448 (2017). • Nijhof IS, van De Donk N, Zweegman S, Lokhorst HM. Current and new therapeutic strategies for relapsed and refractory multiple myeloma: an update. Drugs 78(1), 19–37 (2018). • Mikhael J. Treatment options for triple-class refractory multiple myeloma. Clin. Lymphoma Myeloma Leuk. 20(1), 1–7 (2020). We agree with your comment “with the addition of CAR and bispecifics, treatment options are now considerably more than they were even a few years ago”. According to your comment, we revised the description as below. “TCE patients have limited treatment options, especially before chimeric antigen receptor T-cell (CAR-T) therapies and bispecific antibodies (BsAbs) become available.” (Second paragraph on Page 4 of the track file of the revised manuscript) 5) Line 114: It is important to highlight the time period in which patients had data collected and not just when the data was captured. The results suggest that patients treated with an initial diagnosis before 2015 were included. This is unclear. Response: In this study, the results do not include the data for patients treated with an initial diagnosis before 2015 (before the study period), because we focused the time period after lenalidomide has become available for NDMM patients in Japan. To clearly define incident NDMM diagnosis in the study period in this study, we excluded patients who did not have any medical record for at least for 3 years or had received anti-myeloma treatments and MM diagnosis before the index date. Moreover, even if we changed the window period of 3 years (to 2 years, 1 year and 6 months), the patient characteristics did not change materially, suggesting minimal possibility of bias. We added description to clarify this point as below. “...Multiple myeloma and malignant plasma cell neoplasms), had ≥6 months follow-up data, and were prescribed bortezomib, lenalidomide, and/or daratumumab after the 1st diagnosis of MM were included in the study. Therefore, the results did not include the data of treated patients with an initial diagnosis before 2015.” (First paragraph of ‘Study population and study period’ on Page 6 of the track file of the revised manuscript) 6) Line 119-120 – Should read “ Patients were excluded from the study if they were prescribed anti-myeloma treatment drugs other than dexamethasone and prednisone before index date” Line 124 – The definition of index date should be moved up to before the concept is first utilized (page 6 line 120). To make it easier for the reader. Response: We agree with your suggestion. We moved the definition of index date up just after explaining the study period and inclusion criteria. Therefore, the results do not include the data of treated patients with an initial diagnosis before 2015. The index date was defined as the earliest prescription date of the 1st-line drugs in the same month or months after the first diagnosis of MM. (First paragraph of ‘Study population and study period’ on Page 6 of the track file of the revised manuscript) 7) Line 150 – Authors mentioned that the number of transfusions was a variable of interest, but this was never addressed. Response: We apologize for this error. We deleted transfusion and corrected this description as follows: “Specific outcome variable of interest was TCE status in each line.” (Paragraph above ’Statistical analysis’ on Page 8 of the track file of the revised manuscript) 8) Page 9; Study population – Although Figure 1 does a great job at explaining the breakdown of patients, the text is a little confusing and should be rewritten. Response: We have rewritten the text to explain the study population as below. Over the study period, 44,897 patients had a confirmed diagnosis of MM, of which 16,021 patients had prescriptions for daratumumab, lenalidomide, and/or bortezomib at the index date (Fig 1). Of 12,255 patients who had a follow-up period of at least 6 months from the index date, 10,471 patients who met the other three exclusion criteria—were prescribed anti-myeloma treatment drugs other than dexamethasone and prednisone before the index date , had no medical records before the index date for ≥3 years, and received SCT before the index date—were excluded. Thus, 1,784 patients were included in the final cohort analysis set. Of the 1,784 patients, 1,656 patients were transplant ineligible (non-transplant group) and 128 patients were transplant eligible (transplant group) (Fig 1). (‘Study population’ paragraph on Page 10 of the track file of the revised manuscript) 9) Line 188: Again, this is a very skewed population. Is autoHSCT not standarly used in Japan? Response: This is a limitation of this study. As Japanese patients with MM are elderly (with median age >75 years) and have multiple comorbidities, around 20% of NDMM patients are eligible for transplantation. Furthermore, in this study, NDMM patients who had a follow-up period of at least 6 months from the index date have been selected. When the patients had shorter follow-up period, the medical record for transplantation might not be detected even if the patients have received transplantation. Therefore, the number of transplant eligible patients may be underestimated. We have added this as limitation as below. Second, in Japan, around 20% of NDMM patients are eligible for transplantation [5,22]. This study selected patients with NDMM with ≥6 months follow-up from the index date; therefore, patients with shorter follow-up would be excluded even if they were eligible Attachments Attachment Submitted filename: Res to Reviewers comment_9Aug2024_clean.docx https://doi.org/10.1371/journal.pone.0310333.r002
29 Aug 2024 Decision Letter - Mehmet Baysal, Editor Real-world treatment trends and triple class exposed status in newly diagnosed multiple myeloma patients in Japan: a retrospective claims database study. PONE-D-24-24880R1 Dear Dr. Moribe, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Mehmet Baysal Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #2: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #2: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #2: I have no more additional comments. Thanks to the authors. I think this study will provide interesting data on the approach to MM in Japan. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #2: No ******** https://doi.org/10.1371/journal.pone.0310333.r003
Formally Accepted
22 Sep 2024 Acceptance Letter - Mehmet Baysal, Editor PONE-D-24-24880R1 PLOS ONE Dear Dr. Moribe, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Mehmet Baysal Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0310333.r004

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .